JP6948725B2 - Instruments and methods for the production and concentration of particulate aerosols - Google Patents

Description

<Support from the government>
Part of the present invention is supported by the National Institutes of Health, Heart, Lung and Blood Institute with grant R43HL127834. The US Government has certain rights to the invention.

<Background of invention>
About 200,000 Americans suffer from acute respiratory distress syndrome (ARDS) each year. Recent global studies have shown that ARDS is underdiagnosed and that 10.4% of all patients meet ARDS criteria and are admitted to the intensive care unit (ICU). Symptoms of ARDS include pulmonary diastolic dysfunction, pulmonary edema, increased pulmonary dead space and hypoxemia. Despite sophisticated intensive care, many patients with mild hypoxemia (PaO2 / FiO2 between 200 mmHg and 300 mmHg) worsen to ARDS with PaO2 / FiO2 below 200 mmHg. Despite improved low tidal volume ventilation maintenance, the case fatality rate remains at 30-40%.

Although the etiology of ARDS is often multifactorial, common to ARDS patients is the deterioration of surfactant's surface tension-reducing effect caused by reduced surfactant function and continuous inflammation. The amount of aerated lungs available for gas exchange and mechanical ventilation is reduced primarily by pulmonary diastolic dysfunction in the lower lung region. The low surface tension of surfactant helps maintain the patency of the induced airways and allows the alveoli to open with less respiratory work. Therefore, aerosol surfactant replacement therapy may provide a life-saving treatment.

However, clinical trials of surfactant aerosols for the treatment of ARDS have not shown the expected clinical effect of surfactant administration. The factors behind this result are as follows.
-Insufficient rate of surfactant delivery to the lungs.
• Surfactant has not been administered throughout the period of long-term surfactant abnormalities.
The delivery of surfactant in a non-invasive manner is believed to allow physicians to provide improved life support and potentially significant improvement in life extension.

Aerosol delivery of surfactant to the lungs may benefit other patients with pulmonary dysfunction. This includes treatment of patients with idiopathic pulmonary fibrosis, with a prevalence of 13-20 / 100,000 and up to 60,000 patients in the United States. In addition, the surfactant aerosol may have therapeutic utility in patients with neonatal respiratory distress syndrome (NRDS), chronic obstructive pulmonary disease, asthma, cystic fibrosis and pneumonia. In-hospital respiratory infections are a major health problem, costing an estimated $ 600 million annually. Treatment of such respiratory infections with inhalable aerosol delivery of anti-infective agents using systems such as ^{SUPRAER TM may reduce these medical costs.} Also, if epoprostenol, mucoactive agent and other drugs that form solutions and suspensions can be delivered at high feed rates up to a viscosity of at least 39 cSt in a clinical environment, prior art. It will be an improvement over the technology. In addition, delivering surfactant with the drug may increase the effectiveness of the drug.

Biopharmaceuticals make up 50% of the drug discovery pipeline. At least 60 of the biopharmaceuticals are developed for the treatment of lung disease by intravenous delivery rather than aerosols. Due to the constraints of existing aerosol delivery systems and fixed awareness within the pharmaceutical industry, the venous route is most often selected for the treatment of lung disease with biopharmaceuticals. However, intravenous administration is not only quite resistant to the patient, but also has associated complications. Intravenous administration is likely to require 10 to 100 times higher doses than administration by aerosol inhalation. The ability to deliver these drugs directly to the lungs in the form of inhalable aerosols significantly reduces not only systemic toxicity, but also the total dose of the drug and the cost of treatment.

Non-small cell lung cancer is treated with a mixture of drugs delivered intravenously. Twenty-four types of biologics for lung cancer are in clinical trials, and 12 types are on the market.
For intravenous administration
・ 2 to 15% treat the lungs
-> 85% acts on other organs
・ The dose is 10 to 100 times that of aerosol inhalation.
In the case of aerosol delivery
・ The dose is reduced,
・ Reduced systemic side effects
・ Treatment costs will be lower and better results may be obtained.

The estimated effective dose of surfactant delivered to patients with ARDS by aerosol provides guidance on the dosage rate and total dose of surfactant aerosol required when delivered by an aerosolizer. For newborn lambs, feeding 2 to 7.5 mg / kg of surfactant aerosol has been shown to be effective. Windtree Therapeutics determined that newborns were fed with 100 mg / h or 0.03 mg / s aerosolized surfactant, but only a small amount of it was likely delivered to the lungs. In the case of ARDS, it may be preferable to deliver more surfactant to the lungs, as protein and phospholipase inactivate the surfactant. The mass of surfactant in healthy lungs is estimated to be 5-10 mg / kg. Therefore, for total surfactant replacement in a 70 kg patient, 350-700 mg of surfactant needs to be deposited in the lung. Therefore, it is likely that surfactant aerosols between 300 mg and 1 g should be deposited in the lungs as a suitable therapeutic dose for clinical application in order to be effective. Due to the deterioration of surfactant caused by continuous inflammation, this aerosol surfactant replacement therapy may need to be repeated over and over again.

A sufficient amount of surfactant delivered to an aerosol with an aerodynamic central particle size between 1.5 μm and 4 μm to reach the peripheral lungs and deposit and treat abnormalities and continued loss of surfactant. Salary has been a daunting task for many years. There are various issues to be solved regarding aerosol particle size, administration rate and uniformity of administration rate, as well as aerosol concentration and total output dose.

The output of the ejection sprayer, which produces 3 μm particles and uses the Venturi effect to supply the liquid to the orifice, is low (≤3 ml / min), and decreases as the viscosity of the liquid (surfactant concentration) increases. The concentration of surfactant in the device increases with spraying time. In addition, bubbling can further reduce output.

The viscosity of the surfactant suspension increases sharply as the surfactant concentration increases. The viscosity of high-concentration surfactant suspensions is significantly higher than the viscosity (4cP) that some mesh nebulizers can aerosolize. It took 3 hours to deliver 72 mg of surfactant aerosol at 1.9 μm MMAD.

Windtree Therapeutics uses an aerosol delivery system to deliver aerosolized surfactants to newborns. In this system, disclosed in US Pat. No. 6,234,167 B1, the surfactant suspension is heated and evaporated as it passes through the capillaries. The condensate forms the aerosol to be fed. In neonatal clinical trials of this system, a 3 l / min flow rate produces 100 mg / h (0.03 mg / s), or 0.6 mg / l of surfactant aerosol.

Methods for producing high concentrations of particulate aerosols are disclosed in US Pat. No. 8,596,268 B2, and US Pat. No. 8,596,268 B2 is incorporated herein by reference in its entirety. Briefly, a syringe pump is used to supply the aqueous / aqueous suspension to the aerosolization nozzle. This nozzle aerosolizes 100% of the liquid to form a liquid aerosol with _{a narrow size distribution (σ g <2).} This aerosol eruption is stopped by a coaxial countercurrent of gas. The liquid is evaporated from the particles by a combination of warm compressed and diluted gases and infrared rays whose wavelength is optimized for the absorption band of water. The resulting dry particle aerosol is concentrated using a multi-slit virtual impactor with radially aligned acceleration and deceleration nozzles. The particles gain momentum as they pass through the acceleration nozzle. As the particles pass through the deceleration nozzle, they pass through a small gap and stall, forming a slow aerosol. Most gas escapes from the aerosol stream through the gaps between these nozzles. As such, slow aerosols consist of fairly high concentrations of particles contained in a smaller volume of gas. This aerosol flows out of the port at 3 water columns cm, where it can be aspirated on demand. However, for deep lung deposition in patients with pulmonary dysfunction, with smaller diameter aerosols, higher feeding rates and higher total payloads are needed to treat patients with ARDS and other lung syndromes and diseases. Is desirable. Therefore, an object of the present invention is to produce smaller particles at higher concentrations with higher efficiency and higher payload suitable for clinical use.

To improve the effectiveness of bronchial dilators and gas exchange in patients with pulmonary dysfunction and to promote aerosol deposition in the peripheral lungs, thereby providing a powerful option for the delivery of therapeutic aerosols. Heliox, a mixture of helium and oxygen, typically consisting of 80% helium and 20% oxygen or 70% helium and 30% oxygen is used. Studies using 70/30 heliox for constant atomizer gas flow for aerosol formation have shown that heliox produces larger particles compared to air at all flow rates tested. However, by utilizing the inventions described herein, at the same compressed gas pressure, Heliox achieves a significant reduction in aerosol particle size compared to air.

Virtual impactors for concentrating many aerosols have already been disclosed. For example, some linear slit concentrators use a convergent flow path with a rectangular V-shaped design, as described above. The mass load of the concentrated aerosol can reduce the efficiency of the concentrator and can lead to nozzle clogging at concentrations above 1 mg / L. Aerosols are preferably already in high concentration before they are concentrated due to the high payload delivery. During the production and delivery of the specified payload, the deposition of aerosol on the surface of the concentrator shall not impair the function of the concentrator. Aerosol concentrators satisfying the performance of the present invention have not yet been disclosed.

Since virtual impactors depend on the inertia of aerosol particles, it is difficult to achieve high efficiency in enriching particles smaller than 4 μm MMAD, especially at low pressure differences. For simplification and clinical utility, when the aerosol is concentrated by virtual impaction , the aerosol is pumped to the patient with a slight positive pressure without the use of a pump to remove the exhaust gas. It is desirable that concentration be achieved at a low positive pressure so that it can be achieved. This condition, basically, the use of virtual impactor of high flow resistance such as virtual impactor with circular orifices is eliminated. Slit-type orifices are used in the present invention because they have much lower resistance to gas flow. Aerodynamically designed acceleration and deceleration nozzles reduce resistance to flow and improve the efficiency of the concentrator. U.S. Pat. No. 8,375,987 meets this precondition and is incorporated herein by reference in its entirety. However, the present invention provides the production and processing of smaller particles that can be fed with a higher payload, have lower wall losses and a higher aerosol concentration.

As described above, the technique for feeding a surfactant aerosol for inhalation does not incorporate the technique of the present invention, nor does it provide the aerosol concentration or feeding standard contained in the present invention.

One object of the present invention is an inhalable aerosol production system and a method for producing an inhalable dry powder aerosol thereof, and a) producing small diameter particles from a solution or suspension, and b) then drying an inhalable particle size. To produce powdered aerosols, it improves heat transfer and mass transfer, thereby improving the rate of liquid evaporation from the liquid aerosol, c) reducing aerosol wall loss, d) increasing the efficiency of aerosol concentration, e ) The pressure difference between the input and output and the pressure difference between the input pressure and the environmental pressure are small, and f) By creating a processing system that realizes a high aerosol feed rate of ultrafine particles with higher efficiency and payload than previously achieved. be.

One object of the present invention is to use a cylindrical linear single slit virtual impactor with a high concentration of 1.5-4 μm aerodynamics with an output of at least up to 2 g with an efficiency of greater than 58% while avoiding acoustic resonance. A central particle size aerosol is produced and fed at a flow rate of 10 to 50 liters per minute.

One object of the present invention is to form a two-stage concentrator that produces a high concentration of 1.5 to 6 μm MMAD aerosol at the exhaust outlet of any concentrator without the use of an auxiliary fan or flow control device.

According to one aspect of the invention, an aerosol generation system for producing an inhalable dry powder aerosol from a solution or suspension at a volumetric flow rate, designed to receive the solution or suspension. A liquid aerosol generation nozzle having a nozzle input end, a nozzle gas supply unit designed to receive nozzle gas, and a nozzle output end for outputting a liquid aerosol floating in the nozzle gas, and a liquid aerosol generation nozzle floating in the nozzle gas. A cylindrical evaporation chamber input end connected to the nozzle input end and the dilution gas supply unit to receive both the liquid aerosol and the diluting gas, and the primary intermediate dry powder aerosol to the primary intermediate dry powder aerosol volume flow rate and the primary intermediate dry powder. Cylindrical Evaporation Chamber with Outflow End of Aerosol Particle Concentration Cylindrical Linear Single Slit Cylindrical Linear Single Slit Connected to Output End of Aerosol Concentrator Cylindrical Linear Single Slit An aerosol concentrator, a cylindrical linear single-slit aerosol concentrator, is a cylindrical wire connected from the input end of the cylindrical linear single-slit aerosol concentrator to the cylindrical linear single-slit aerosol concentrator aerosol separation space. Convergent Cylindrical Linear Single Slit Aerosol Concentrator Converging towards the Input orifice, Cylindrical Linear Single Slit Aerosol Concentrator Aerosol Separation Space is Cylindrical Linear Single Slit Aerosol Concentrator Connected to both the outlet and the cylindrical linear single-slit aerosol concentrator output orifice, the cylindrical linear single-slit aerosol concentrator output orifice is lower than the primary intermediate dry powder aerosol volume flow rate and can be sucked dry powder aerosol volume flow rate. A divergent cylindrical linear single-slit aerosol concentrator that outputs a dry powder aerosol that can be inhaled at a concentration of dry powder aerosol particles that is higher than the primary intermediate dry powder aerosol particle concentration. An aerosol generation system with a single-slit aerosol concentrator is provided.

According to another aspect of the invention, a corresponding method of producing an inhalable dry powder aerosol from a solution or suspension at a volumetric flow rate, wherein the solution or suspension and the nozzle gas are liquid aerosols. The liquid aerosol that is supplied to the generation nozzle and floats in the nozzle gas is output from the liquid aerosol generation nozzle to the cylindrical evaporation chamber, the dilution gas is supplied to the cylindrical evaporation chamber, and the medically effective drug is supplied from the cylindrical evaporation chamber. A primary intermediate dry powder aerosol having fine dry powder particles suspended in a gas, which makes the contained particles inhalable, is output at a volume flow rate of the primary intermediate dry powder aerosol and a concentration of the primary intermediate dry powder aerosol particles, and is output as a primary intermediate dry powder aerosol. Is supplied to the cylindrical linear single-slit aerosol concentrator, and the cylindrical linear single-slit aerosol concentrator converges toward the cylindrical linear single-slit aerosol concentrator input orifice. Concentrator Input Path and Cylindrical Linear Single Slit Aerosol Concentrator Equipped with a divergent cylindrical single slit aerosol concentrator output path diverging from the output orifice, primary intermediate dry powder aerosol volume Inhalable dry powder aerosol volume lower than the flow rate Provided is a method of outputting an inhalable dry powder aerosol at a flow rate and at a concentration of inhalable dry powder aerosol particles higher than the concentration of primary intermediate dry powder aerosol particles.

According to another aspect of the invention, the cylindrical linear single-slit aerosol concentrator can be combined with a cylindrical radial multi-slit aerosol concentrator. This configuration is capable of concentrating high volumetric flow rates, especially in the first stage, with a cylindrical radial multi-slit aerosol concentrator, and then concentrating lower volumetric flow rates with a cylindrical linear single-slit aerosol concentrator. There is an advantage. This configuration also allows both concentrators to operate with high efficiency so that the total efficiency of this two-step enrichment is very high, for example well over 80%.

Further, according to another aspect of the invention, the systems and methods include heliox supplied from one or more heliox sources, especially as a diluent gas and also as a nozzle gas for aerosolizing the suspension. But it's okay. A specific advantage of heliox other than the more favorable Reynolds number of heliox, which makes the flow more layered and thereby allows for higher concentrator efficiency, is that the liquid aerosol is treated in the evaporation chamber, which is later preferred by the present invention. High specific heat and low specific gravity that allow the drying process to be accelerated in making a dry powder aerosol that can be concentrated according to embodiments. Heliox works well in all types of concentrators, specifically both cylindrical linear single-slit aerosol concentrators and cylindrical radial multi-slit aerosol concentrators, but according to the invention in particular. Works well compared to air in cylindrical linear single-slit aerosol concentrators.

<Detailed description of the invention>
The liquid to be aerosolized is pumped from the solution or suspension container to the nozzle input end on the nozzle holder, from which it flows through the central flow path to the liquid nozzle. The compressed gas enters the nozzle holder through the two gas inlet orifices on the nozzle holder, is transferred to the annular pressure balancing chamber through at least two gas channels in the nozzle holder, and through the annular convergence channel. It is transferred to the annular divergence flow path and finally to the aerosolized space between the liquid nozzle and the nozzle output end. This configuration is specified for the liquid aerosol generation nozzle. The compressed gas may or may not be heated. Details of this nozzle holder and liquid aerosol generation nozzle are described in more detail in US Patent Application No. 15 / 130,235. The solution or suspension to be aerosolized and the compressed gas interact in the aerosolizing space to form a liquid aerosol. This liquid aerosol passes through the center of the nozzle output end and exits the aerosolized space. A sheath of gas containing few particles surrounds the liquid aerosol so that it does not come into contact with the nozzle output edge. In a suitable configuration, the gas is air or heliox.

で表され、ρはガス密度、vはカスの速度、dは特性寸法、σは液体の表面張力である。ρ_air＝1.28kg/m³、ρ_heliox＝0.4kg/m³である。空気又はヘリオックスと接している水の表面張力は類似しておりσ≒73mN/mである。Weはヘリオックスが空気の1.62倍高く、従って同じガス圧ではヘリオックスの方が小さい粒子を生成すると予測される。 The Weber number We provides a measure of how efficiently the gas atomizes the liquid.

Represented by, ρ is the gas density, v is the velocity of the residue, d is the characteristic dimension, and σ is the surface tension of the liquid. ρ _air = 1.28kg / m ^3, a _ρ heliox = 0.4kg / m ^3. The surface tension of water in contact with air or heliox is similar, σ ≈ 73 mN / m. We predict that heliox is 1.62 times higher than air, so at the same gas pressure heliox produces smaller particles.

で算出することができ、k＝比熱比であり、空気はk＝1.4、ヘリオックスはk＝1.58である。また、R＝ガス定数であり、空気はR＝287J/kg・K、ヘリオックスはR＝1546J/kg・Kである。更に、T_o＝上流温度、P＝下流圧力、P_o＝上流滞留圧力である。下流圧力がP＝14.7psi＝1.01×10⁵Pa、上流圧力がP_o＝25psi＝1.72×10⁵Pa、上流ガス温度がT_o＝20℃＝293Kの場合、ノズルの出口における空気の速度はv_air＝287m/s、ヘリオックスの速度はv_heliox＝661m/sである。従って、ヘリオックスの速度が2.3倍高くなる。ヘリオックスのWeは空気の1.64倍である。そのため、同じ駆動圧力では、ヘリオックスの方が小さい粒子を生成する。サーファクタントの、水と比較して非常に低い表面張力は、ウェーバー数及び噴霧化効率の更なる増加につながる。 The velocity of the gas at the outlet of the nozzle

It can be calculated by, k = specific heat ratio, air is k = 1.4, and heliox is k = 1.58. In addition, R = gas constant, air is R = 287J / kg · K, and heliox is R = 1546J / kg · K. Furthermore, T _o = upstream temperature, P = downstream pressure is P _o = upstream dwell pressure. Downstream pressure ^{P = 14.7psi = 1.01 × 10 5} Pa, the upstream pressure _{P o = 25psi = 1.72 × 10} 5 Pa, when the upstream gas temperature is T _o = 20 ℃ = 293K, the rate of air at the outlet of the nozzle v _air = 287m / s, the velocity of Heliox is v _heliox = 661m / s. Therefore, the speed of Heliox is 2.3 times higher. Heliox's We is 1.64 times that of air. Therefore, at the same driving pressure, Heliox produces smaller particles. The very low surface tension of surfactant compared to water leads to a further increase in Weber number and atomization efficiency.

The liquid aerosol coming out of the nozzle output end forms an aerosol jet that is stopped by a coaxial countercurrent jet of compressed gas coming out of a countercurrent orifice located about 5 cm from the liquid aerosol generating nozzle. The liquid aerosol thus dispersed enters the cylindrical evaporation chamber through a flow distributor designed to provide a relatively uniform gas flow through the cylindrical evaporation chamber surrounding the nozzle holder, preferably warm and dry. It is transferred through a cylindrical evaporation chamber by the stream of diluted gas. Infrared rays of wavelengths within the absorption band of water provided by the infrared source are transmitted through the walls of the cylindrical evaporation chamber. This infrared ray, along with a warm, dry gas, evaporates water from the droplets to form a primary intermediate dry powder aerosol. In the absolutely dry state, these primary intermediate dry aerosols may or may not be solid spherical particles, mainly depending on the drying rate and the physicochemical properties of the aerosolized solution or suspension. Of course, if the droplets are not completely evaporated, the size of the liquid aerosol will be smaller than the originally produced liquid aerosol. In a suitable configuration, the gas is heliox. The specific heat capacity of air is 1.0 kJ / kg · K, while the specific heat capacity of Heliox is 4.3 kJ / kg · K. The thermal conductivity of helium is about 6 times higher than that of air (0.02 W / m · K vs. 0.149 W / m · K). The diffusion coefficient of water vapor in helium is 3.3 times higher than in air. In addition, the convective thermal conductivity depends on the gas flow around the droplets. An increase in the flow of compressed gas from the liquid aerosol generation nozzle and the resulting increase in the rate of countercurrent gas increases the rate of evaporation of water from the droplets. Therefore, if the compressed gas pressure and nozzle output end diameter are the same, using heliox instead of air to generate and process the aerosol reduces the time it takes to evaporate the liquid from the initial droplets, resulting in Reduced particle loss due to inertial impaction and deposition within the aerosol treatment system. This is the first configuration of the present invention. This primary intermediate dry powder aerosol can be used as it exits the cylindrical evaporation chamber through the output end of the cylindrical evaporation chamber.

A second configuration of the present invention includes an aerosol processing system comprising a liquid aerosol generating nozzle, a countercurrent tube, a flow distributor, a cylindrical evaporation chamber and a cylindrical linear single slit aerosol concentrator. In this second configuration of the present invention, the primary intermediate dry powder aerosol is delivered from the output end of the cylindrical evaporation chamber through the input end of the cylindrical linear single-slit aerosol concentrator into a cylindrical linear single-slit aerosol concentrator. Moving. Cylindrical linear single-slit aerosol concentrators work on the principle of virtual impaction. In this cylindrical single-slit aerosol concentrator, the velocity of the primary intermediate dry powder aerosol entering the cylindrical single-slit aerosol concentrator increases as it passes through the convergent cylindrical linear single-slit aerosol concentrator input path. In a preferred configuration, this convergent cylindrical single-slit aerosol concentrator input path is suitable for engraving channels that are 3.25 inches long, have a circular inlet 70 mm in diameter, and have a gradual decrease in cross-sectional area. Cylindrical linear single-slit aerosol concentrator input orifice with slits that are 32 mm long and 1.3 mm wide and may be between 0.2 cm and 6 cm in length and 1 mm to 2 mm in width in the configuration. Be prepared. In a preferred configuration, the angle of the wall with respect to the center of the cylindrical linear single slit aerosol concentrator input orifice is 21 degrees, but other angles between 10 and 60 degrees are possible. This cylindrical linear single-slit aerosol concentrator has the same length as the input orifice and a width of 1.6 mm, which is slightly wider than the cylindrical linear single-slit aerosol concentrator input orifice. , Cylindrical Linear Single Slit Aerosol Concentrator Aligned parallel to this at a distance of 1.7 mm from the input orifice. Cylindrical Linear Single Slit Aerosol Concentrator Large enough to form a cylindrical linear single slit aerosol concentrator aerosol separation space between the input orifice and the cylindrical linear single slit aerosol concentrator output orifice to reduce resonance. There is a longitudinal cylindrical linear single-slit aerosol concentrator aerosol separation space that is optimized and preferably between 1 mm and 2 mm in a preferred configuration of 1.7 mm. The cylindrical linear single-slit aerosol concentrator output orifice is the inlet of the divergent cylindrical single-slit aerosol concentrator output path. The divergent cylindrical linear single-slit aerosol concentrator output path is, in a suitable configuration, a 5 cm long engraving deceleration channel ending at a circular outlet with an outer diameter of 35 mm, but other lengths are possible. be. In a preferred configuration, the angle of the wall with respect to the center of the cylindrical linear single slit aerosol concentrator output orifice is 20 degrees, but may be between 10 and 60 degrees. This small divergence angle minimizes backflow. The primary intermediate dry powder aerosol passes through the convergent cylindrical linear single slit aerosol concentrator input path and through the cylindrical linear single slit aerosol concentrator input orifice to the cylindrical linear single slit aerosol concentrator aerosol separation space. Accelerate by appearing in. The momentum of the primary intermediate dry powder aerosol causes most aerosols to cross the cylindrical linear single-slit aerosol concentrator aerosol separation space and enter the cylindrical linear single-slit aerosol concentrator output orifice to diverge cylindrical linear. Single-slit aerosol concentrator Allows entry into the output path. The primary exhaust aerosol, which contains most gases, exits the primary intermediate dry powder aerosol on each side of the cylindrical linear single-slit aerosol concentrator aerosolization space to enter the engraving plenum, along with a very small amount of floating particles. To go. The preferred volume of engraving plenum is 170 ml, but volumes between 30 ml and 300 ml are possible. The advantage of this configuration is that when the slits of this cylindrical linear single-slit aerosol concentrator are vertically oriented, the wall loss due to gravity in the convergent cylindrical linear single-slit aerosol concentrator input path is minimal. That is. The primary effluent aerosol flowing through the engraving plenum has a significantly reduced aerosol concentration compared to the concentration of primary intermediate dry powder aerosol particles. This engraving plenum contains a small amount of particles entering a cylindrical linear single-slit aerosol concentrator, which is substantially the flow of the primary intermediate aerosol across the cylindrical linear single-slit aerosol concentrator aerosol separation space. Has sufficient volume to not interfere with the aerosol. The primary exhaust aerosol exits the engraved plenum through a cylindrical linear single-slit aerosol concentrator outlet with a diameter of 15 mm in a suitable configuration. The size of this outlet suppresses the generation of resonant standing waves within the engraved plenum.

で表され、Φ＝インパクションパラメータ（無次元）、C＝ガス分子の平均自由行程に匹敵するサイズの粒子のカニンガムの補正係数、ρ_p＝粒子の比重（g/cm³）、d_p＝粒子径（cm）、v＝噴出速度（cm/sec）、D_jは噴射径（cm）、μ＝ガスの粘度（Pa・s）であり、μ_air＝18×10⁶Pa・s、μ_heliox＝19.1×10⁶Pa・sと、ヘリオックスと空気の粘度は類似している。空気の相対レイノルズ数はヘリオックスの3.2倍である。円筒型蒸発チャンバと一次排出エアロゾルの間だけでなく円筒型線状単スリットエアロゾル濃縮器全体を通して低圧力差で円筒型線状単スリットエアロゾル濃縮器が高ヘリオックス流量で動作することを可能にする。発散型円筒型線状単スリットエアロゾル濃縮器出力路から出る吸入可能乾燥粉末エアロゾルは、その吸入可能乾燥粉末エアロゾル体積流量が発散型円筒型線状単スリットエアロゾル濃縮器出力路に接続されたエアロゾル受け装置によって制限されている状態で低い正圧を有する。吸入可能乾燥粉末エアロゾルは、発散型円筒型線状単スリットエアロゾル濃縮器出力部を円筒型線状単スリットエアロゾル濃縮器回収コーン、フィルタ又は器具に接続することで、或いは哺乳類により吸入されることにより出力することができる。 The impaction parameters for aerosols are

Represented by, Φ = impaction parameter (non-dimensional), C = correction coefficient of Cunningham of particles of a size comparable to the mean free path of gas molecules, ρ _p = specific gravity of particles (g / cm ³ ), d _p = Particle size (cm), v = ejection velocity (cm / sec), D _j is injection diameter (cm), μ = gas viscosity (Pa · s), μ _air = 18 × 10 ⁶ Pa · s, μ _Heliox = 19.1 × 10 ⁶ Pa · s, and the viscosity of heliox and air is similar. The relative Reynolds number of air is 3.2 times that of Heliox. Allows the cylindrical linear single-slit aerosol concentrator to operate at high heliox flow rates with low pressure differences throughout the cylindrical linear single-slit aerosol concentrator as well as between the cylindrical evaporation chamber and the primary discharge aerosol. .. The inhalable dry powder aerosol coming out of the divergent cylindrical single slit aerosol concentrator output path is the aerosol receiver whose inhalable dry powder aerosol volume flow is connected to the divergent cylindrical linear single slit aerosol concentrator output path. Has a low positive pressure in conditions restricted by the device. Inhalable dry powder aerosols can be obtained by connecting the divergent cylindrical single slit aerosol concentrator output to a cylindrical linear single slit aerosol concentrator recovery cone, filter or instrument, or by inhalation by a mammal. Can be output.

In the third configuration of the present invention, the cylindrical radial multislit aerosol concentrator is cylindrically evaporated so that the primary intermediate dry powder aerosol from the output end of the cylindrical evaporation chamber enters the input end of the cylindrical radial multislit aerosol concentrator. It is attached to the output end of the chamber. An important feature of this cylindrical radial multislit aerosol concentrator was previously described in US Pat. No. 8,375,987, and US Pat. No. 8,375,987 is incorporated herein in its entirety. The cylindrical radial multi-slit aerosol concentrator has 16 accelerating slit orifices. In this configuration, the primary intermediate dry powder aerosol is transferred from the output end of the cylindrical evaporation chamber to the input end of the cylindrical radial multislit concentrator, from which it is transferred to a radially aligned acceleration nozzle, where the aerosol is accelerated. Particles contained in the primary intermediate dry powder aerosol enter a deceleration nozzle that is radially aligned across the aerosol separation space in a cylindrical radial multi-slit aerosol concentrator between the acceleration slit orifice and the deceleration slit orifice, where the primary intermediate dry powder aerosol volume. The flow rate is reduced to form a secondary intermediate dry powder aerosol. Secondary effluent aerosols containing gas and low proportion particles exit through the cylindrical radial multi-slit aerosol concentrator aerosol separation space between the accelerating slit orifice and the deceleration slit orifice and enter the circular plenum into the circular plenum. It is discharged through a cylindrical radial multi-slit aerosol concentrator outlet on the wall. The volumetric flow rate of the secondary intermediate dry powder aerosol is controlled by an external device connected to the output end of the cylindrical radial multislit concentrator, and the secondary intermediate dry powder aerosol is output through the external device.

In the fourth configuration of the present invention, the input end of the cylindrical linear single-slit aerosol concentrator of the cylindrical linear single-slit aerosol concentrator is connected to the output end of the cylindrical radial multi-slit aerosol concentrator. If a cylindrical radial multi-slit aerosol concentrator and a cylindrical linear single-slit aerosol concentrator are connected, they will have a two-stage concentrator. In a preferred configuration, the total slit length of the slits in the cylindrical radial multi-slit aerosol concentrator is 141 mm, whereas the slit length in the cylindrical linear single-slit aerosol concentrator is 32 mm, a ratio of 4.4 pairs. Although it is 1, a ratio between 2: 1 and 6: 1 is possible. Cylindrical Linear Single Slit Aerosol Concentrator The width of the output orifice and the width of the deceleration slit orifice of the cylindrical radial multi-slit aerosol concentrator are similar, and compared with the cylindrical radial multi-slit aerosol concentrator aerosol separation space. Cylindrical Linear Single Slit Aerosol Concentrator Similar to the similar aerosol separation space, cylindrical linear single slit aerosol concentrator input orifice width and cylindrical radial multi-slit aerosol concentrator acceleration slit orifice The width is also similar. Assuming this configuration, when the inhalable dry powder aerosol volume flow rate of the cylindrical linear single-slit aerosol concentrator, which is the second stage, is set, the aerosol at each stage and the outlet corresponding to each stage. The volumetric flow distribution is such that the ratio of input to output in each concentrator is significantly lower than that of a monoconcentrator with a much higher ratio of input to output.

In this fourth configuration, the secondary intermediate aerosol from the radially aligned deceleration nozzle enters the convergent cylindrical linear single-slit aerosol concentrator input path, where the secondary intermediate aerosol is convergent cylindrical linear. Accelerates through the single-slit aerosol concentrator input path towards the cylindrical linear single-slit aerosol concentrator input orifice. As explained earlier, most of the particles coming out of the cylindrical linear single-slit aerosol concentrator input orifice cross the cylindrical linear single-slit aerosol concentrator aerosol separation space and the cylindrical linear single-slit aerosol concentrator output path. Through the divergent cylindrical single-slit aerosol concentrator output path, the primary discharge aerosol exits the cylindrical linear single-slit aerosol concentrator aerosol separation space and flows into the engraving plenum and through the engraving plenum. , Flows into a cylindrical linear single-slit aerosol concentrator outlet on the outer wall of the engraved plenum. Divergent Cylindrical Linear Single Slit Aerosol Concentrator The volumetric flow rate of inhalable dry powder aerosol from the output path is controlled outside the cylindrical linear single slit aerosol concentrator and includes inhalable dry powder aerosol.

The advantage of the two-stage configuration is that the ratio of the input aerosol volume flow rate to the output aerosol volume flow rate at each stage is lower than when only the cylindrical radial multi-slit concentrator is used at a considerably higher input volume flow rate to output volume flow rate ratio. That is. The efficiency with the two-stage concentrator is higher than with the one-stage cylindrical radial multi-slit aerosol concentrator, and the pressure at the second-stage output end is also much lower. These features improve the practicality and adaptability of this configuration.

Cylindrical linear single-slit aerosol concentrators are used for a) heliox, b) for low-volume air administration when low output is desired, such as when delivering aerosols to infants, children, animals, etc., and c) the present application. When connected in series with the cylindrical radial multi-slit concentrator, it can be used as a component of a two-stage concentrator.

FIG. 1A is a perspective view of an aerosol generation system according to an embodiment of the present invention. FIG. 1B is a top view of the embodiment shown in FIG. 1A. FIG. 1C is a longitudinal sectional view of HH in FIG. 1B. FIG. 2A is a perspective view of an aerosol generation system according to an embodiment of the present invention, which comprises a cylindrical linear single-slit aerosol concentrator. FIG. 2B is a top view of the embodiment shown in FIG. 2A. FIG. 2C is a longitudinal sectional view of I-I in FIG. 2B. FIG. 3A is a perspective view of the liquid aerosol generation nozzle and flow distributor subassembly included in the embodiment of the present invention. FIG. 3B is a front view of the subassembly shown in FIG. 3A. FIG. 3C is a longitudinal sectional view of BB in FIG. 3B. FIG. 3D is a longitudinal sectional view of CC in FIG. 3B. FIG. 4A is a perspective view of the liquid aerosol generation nozzle and nozzle subassembly included in the embodiment of the present invention. FIG. 4B is an exploded perspective view of the subassembly shown in FIG. 4A. FIG. 4C is a side view of the subassembly shown in FIG. 4A. FIG. 4D is a longitudinal sectional view of FF in FIG. 4C. FIG. 4E is a detailed structural diagram of A in FIG. 4D. FIG. 5A is a perspective view of a cylindrical linear single slit aerosol concentrator subassembly included in the embodiment of the present invention. FIG. 5B is an exploded perspective view of the subassembly shown in FIG. 5A. FIG. 5C is a side view of the subassembly shown in FIG. 5A. FIG. 5D is a longitudinal sectional view of DD in FIG. 5C. FIG. 6A is a perspective view of an aerosol generation system according to an embodiment of the present invention, which includes a cylindrical radial multi-slit aerosol concentrator. FIG. 6B is a top view of the embodiment shown in FIG. 6A. FIG. 6C is a longitudinal sectional view of GG in FIG. 6B. FIG. 7A is a perspective view of an aerosol generation system according to an embodiment of the present invention, which includes both a cylindrical radial multi-slit aerosol concentrator and a cylindrical linear single-slit aerosol concentrator arranged in series. FIG. 7B is an exploded perspective view of the aerosol generation system shown in FIG. 7A. FIG. 7C is a top view of the aerosol processing system of the aerosol generation system shown in FIG. 7A. FIG. 7D is a longitudinal sectional view of AA in FIG. 7C. FIG. 8A is an exploded front perspective view of the cylindrical radial multi-slit aerosol concentrator. FIG. 8B is an exploded rear perspective view of the cylindrical radial multislit aerosol concentrator shown in FIG. 8A. FIG. 8C is a front view of the cylindrical radial multislit aerosol concentrator shown in FIG. 8A. FIG. 8D is a side view of the cylindrical radial multislit aerosol concentrator shown in FIG. 8A. FIG. 8E is a rear view of the cylindrical radial multislit aerosol concentrator shown in FIG. 8A. FIG. 9 shows the effect of compressed gas pressure (CGP) on the aerodynamic central particle size (MMAD) (μm) of aerosol particles in a PVP solution using a cylindrical radial multislit aerosol concentrator. be. Triangular, circular, square and star-shaped dots are KB-N-500 (air), KB-N-500 (heliox), KB-N-600 (air) and KB-N-600 (heliox), respectively. ) Indicates the aerosol produced by the nozzle. In FIG. 10, for both the PVP solution and the surfactant suspension, the aerosolization rate (AR) (unit: ml / min) of the liquid to be aerosolized is the aerodynamic central particle size (MMAD) (unit: μm) of the aerosol particles. ) Is shown in the figure. Square, triangular, circular and star-shaped dots are aerosols generated from 10% 8kDa PVP (air), 9.33% surfactant (air), 10% 8kDa PVP (heliox) and 9.33% surfactant (heliox), respectively. Is shown. FIG. 11 is _{a diagram showing the effect of the viscosity (μ f} ) (unit: cSt) of the liquid to be aerosolized on the aerodynamic central particle diameter (MMAD) (unit: μm) of the aerosol particles. FIG. 12 shows the compressed gas pressure (CGP) for both a 10% 8 kDa PVP solution and an 8.85% surfactant suspension at an aerosolization rate (AR) of 3 ml / min using a cylindrical linear single-slit aerosol concentrator. Is a diagram showing the effect of aerosol particles on the aerodynamic central particle size (MMAD) (unit: μm). Triangular and square dots indicate aerosols produced from 10% 8kDa PVP (Heliox) and 8.85% Surfactant (Heliox), respectively. FIG. 13 shows the rate of aerosolization (AR) dose rate (DR) (unit: mg / mg /) for both 10% 8 kDa PVP solution and 9.33% surfactant suspension using a cylindrical linear single slit aerosol concentrator. It is a figure which showed the influence on min). Square and triangular dots indicate aerosols produced from 10% 8kDa PVP (Heliox) and 9.33% Surfactant (Heliox), respectively. FIG. 14 is a diagram showing the effect of inhalable dry powder aerosol volume flow rate (RAVF) on output efficiency (OE) and mass concentration (MC) using a cylindrical linear single-slit aerosol concentrator.

<Detailed explanation of drawings>
The first configuration of the present invention includes an aerosol generation system including a liquid aerosol generation nozzle 3, a countercurrent tube 54, a flow distributor 5, and a cylindrical evaporation chamber 6, as shown in FIG. The liquid aerosol generation nozzle 3 is described in detail in US Patent Application No. 15 / 130,235. The flow distributor 5 and the cylindrical evaporation chamber 6 are described in US Pat. No. 8,616,532. Each of these applications and patents is incorporated herein by reference in its entirety. A perspective view and a cross-sectional view of the liquid aerosol generation nozzle 3 are shown in FIG. The flow distributor 5 is shown in FIG. The liquid to be aerosolized is supplied into the nozzle input end 11 of the nozzle holder 27 shown in FIG. 1C by pressure. As depicted in FIG. 4E, this liquid flows from the nozzle input end 11 through the central flow path 28 in the nozzle holder 27 to the liquid nozzle 29 and then into the aerosolization space 35. The compressed gas, which may or may not be heated, is provided through the nozzle gas supply unit 55 in the flow distributor 5 (FIG. 3A). This compressed gas flows from the nozzle gas supply unit 55 in the flow distributor 5 to the flow path 56, where the flow is distributed (FIG. 3C). Part of the flow flows through the compressed gas flow path 57 connected to the two compressed gas inlet orifices 30 on the nozzle holder 27 (FIG. 4D). As shown in FIGS. 3C and 4D, the gas in the form of nozzle gas 2 passes through the gas flow path 31 (FIG. 4D) from these gas inlet orifices 30 and the annular pressure equilibration chamber 32 as shown in FIG. 4E. Flow in. The nozzle gas 2 flows from the annular pressure equilibration chamber 32 through the annular converging flow path 33 to the annular divergence flow path 34 and flows into the aerosolization space 35, where it interacts with the liquid entering the aerosolization space 35. The resulting liquid aerosol 13 exits the aerosolization space 35 through the nozzle output end 36 (FIG. 4E) and forms the aerosol eruption column 37 as shown in FIGS. 1C and 3C. As shown in FIG. 3C, the rest of the gas flow flows through the constriction orifice 58, through the counter flow flow path 59, and into the counter flow orifice 38 coaxial with the central flow path 28. This gas forms a jet in the direction opposite to and coaxial with the aerosol jet 37 of the liquid aerosol 13. This jet stops the aerosol eruption 37 of the liquid aerosol 13. This countercurrent gas can be supplied to the liquid aerosol generation nozzle 3 and its flow can be adjusted independently of the compressed gas. As shown in FIGS. 3A and 3D, the diluent gas 4, which may or may not be heated, enters the dilution gas supply section 60 of the flow distributor 5 and flows from there into the donut-shaped chamber 61. It flows through the hole 62 of the first baffle 63 into the second circular chamber 64 and again through the second baffle 65 into the cylindrical evaporation chamber 6 (FIG. 1C). Some gas entering the second circular chamber 64 flows through the hole 66 of the internal cylindrical chamber 67 and from there through the central hole 68 in the central region of the second baffle 65 into the cylindrical evaporation chamber 6. .. The diluting gas 4 passes through both the central hole 68 and the peripheral hole 69 (see FIGS. 3A and 3B) of the second baffle 65, and carries the stopped aerosol eruption 37 together into the cylindrical evaporation chamber 6. Flow and transfer this liquid aerosol 13 through the cylindrical evaporation chamber 6. In a suitable configuration, the cylindrical evaporation chamber 6 is composed of a quartz tube 70 (FIG. 1C) having a length of 23 cm and an outer diameter of 7 cm, but other lengths and outer diameters are also possible. Infrared rays from the infrared source 39 (FIGS. 1A and 1C) adjacent to the cylindrical evaporation chamber 6 are transmitted through the wall of the quartz tube 70. The reflector 72 on the opposite side of the cylindrical evaporation chamber 6 with respect to the infrared source 39 reflects the infrared rays transmitted through the opposite wall of the quartz tube 70 into the cylindrical evaporation chamber 6. The reflector 72 is made of semi-cylindrical aluminum, but other materials and shapes are possible. When the liquid aerosol 13 is diluted by the diluting gas 4 and passes through this radiation region, the water in the droplets evaporates rapidly to form the primary intermediate dry powder aerosol 14. The resulting solid phase primary intermediate dry powder aerosol 14 exits from the output end 8 of the cylindrical evaporation chamber, where the solid phase primary intermediate dry powder aerosol 14 becomes available.

The second configuration of the present invention includes an aerosol generation system including a liquid aerosol generation nozzle 3, a countercurrent tube 54, a flow distributor 5, a cylindrical evaporation chamber 6, and a cylindrical linear single slit aerosol concentrator 9, FIG. 2A. It is shown in ~ 2C. In this configuration, the resulting solid phase primary intermediate dry powder aerosol 14 exits the cylindrical evaporation chamber 6 into a cylindrical linear single slit aerosol concentrator 9 connected to the output end 8 of the cylindrical evaporation chamber. come in. The connection of the cylindrical evaporation chamber input end 7 to the flow distributor 5 and the connection of the cylindrical evaporation chamber output end 8 to the cylindrical linear single slit aerosol concentrator input end 10 are made airtight by using the lip seal 73. There is. The cylindrical linear single-slit aerosol concentrator 9 is engraved so that the end of the flow path is a cylindrical linear single-slit aerosol concentrator input orifice 20 having a slit with a length of 33 mm and a width of 1 mm. Is composed of a convergent cylindrical single-slit aerosol concentrator input path 19 (FIGS. 5A to 5D) having a size of 8.4 cm. The wall-convergent cylindrical single-slit aerosol concentrator input orifice angle 74 (FIG. 2C) and the convergent cylindrical linear single-slit aerosol concentrator input path angle 52 (FIG. 5D) are cylindrical linear single-slit aerosols. 11 degrees to the end of the concentrator input orifice 20 and 21 degrees to the center of the cylindrical linear single slit aerosol concentrator input orifice 20. The cylindrical linear single-slit aerosol concentrator output orifice 21 having a length of 34 mm and a width of 1.4 mm diverges toward the circular outlet 41 to form a divergent cylindrical single-slit aerosol concentrator output path 22. The divergent cylindrical linear single-slit aerosol concentrator output orifice angle 75 and the divergent cylindrical linear single-slit aerosol concentrator output path angle 53 on the wall of the divergent cylindrical single-slit aerosol output path 22 are cylindrical. It is 1.4 degrees to the end of the linear single-slit aerosol concentrator output orifice 21 and 20.3 degrees to the center of the cylindrical linear single-slit aerosol concentrator output orifice 21. The divergent cylindrical single-slit aerosol concentrator output path 22, along with the cylindrical linear single-slit aerosol concentrator output orifice 21, is a convergent cylindrical linear single-slit aerosol concentrator input path 19 and a cylindrical linear single. It is arranged so that it is exactly aligned with the slit aerosol concentrator input orifice 20. Between the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21, there is a 1.7 mm cylindrical linear single-slit aerosol concentrator aerosol separation space 40. Convergent Cylindrical Linear Single Slit Aerosol Concentrator Outer Surface 76 at the End of Input Path 19, Divergent Cylindrical Linear Single Slit Aerosol Concentrator Output Path 22 Outer Surface 77, and Cylindrical Linear Single Slit Aerosol Concentrator 9 There is a sculpture aerosol 43 formed by an inner wall 78. The engraving plenum 43 is a cylindrical linear single-slit aerosol concentrator discharge port aligned with the longitudinal axis of the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21. Has 44. The inner diameter of the cylindrical single-slit aerosol concentrator discharge port 44 is 15 mm. The primary intermediate dry powder aerosol 14 having a primary intermediate dry powder aerosol volume flow rate 89 and a primary intermediate dry powder aerosol particle concentration 90 is a cylindrical linear single slit aerosol through a convergent cylindrical linear single slit aerosol concentrator input path 19. It is accelerated as it flows toward the concentrator input orifice 20 and through the cylindrical linear single slit aerosol concentrator input orifice 20. The momentum of the particles exiting the cylindrical linear single-slit aerosol concentrator input orifice 20 is such that most of the particles, including the primary intermediate aerosol 14, cross the cylindrical linear single-slit aerosol concentrator aerosol separation space 40. It enters the single-slit aerosol concentrator output orifice 21 and makes it possible to form an inhalable dry powder aerosol 15. A very small amount of the primary intermediate dry powder aerosol 14 exits the primary intermediate dry powder aerosol 14 through the cylindrical linear single slit aerosol concentrator aerosol separation space 40 and into the engraving plenum 43 the primary intermediate dry powder aerosol volumetric flow rate. Enter at right angles to the 89 direction to form the primary discharge aerosol 16. The primary discharge aerosol 16 flows through the engraving plenum 43 and exits from the engraving discharge flow path 80 (FIG. 2C) to the cylindrical linear single slit aerosol concentrator outlet 44. The inhalable dry powder aerosol 15 having an inhalable dry powder aerosol volume flow rate 91 and an inhalable dry powder aerosol particle concentration 92 flows into the recovery cone 79 through the divergent cylindrical linear single-slit aerosol concentrator output path 22. The device connected to the recovery cone 79 controls the inhalable dry powder aerosol volume flow rate 91 of the inhalable dry powder aerosol 15.

The third configuration of the present invention includes a liquid aerosol generating nozzle 3, a countercurrent tube 54, a flow distributor 5, a cylindrical evaporation chamber 6, and a cylindrical radial multi-slit aerosol concentrator 24 connected as shown in FIGS. 6A to 6C. Includes an aerosol generation system comprising. A similar cylindrical radial multislit aerosol concentrator 24 is described in US Pat. No. 8,375,987, which is incorporated herein by reference in its entirety. In this third configuration, the cylindrical evaporation chamber output end 8 is connected to the cylindrical radial multislit aerosol concentrator input end 25. The configuration of the cylindrical radial multi-slit aerosol concentrator 24 is shown in FIGS. 8A-8E. The inlet plate 81 has 16 radially aligned acceleration nozzles 45, of which the longer ones extend towards the center and the shorter ones are located closer to the veranda. The radially aligned acceleration nozzles 45 are aerodynamically engraved to reduce aerosol deposition. At the narrowed end of these radially aligned acceleration nozzles 45, there is an acceleration slit orifice 47. These acceleration slit orifices 47 have a width of 1 mm. On the opposite side of the inlet plate 81, an inlet plate flow path 82 adjacent to the circular plenum 50 (FIG. 6C) is formed so that the acceleration nozzles 45 arranged in a radial pattern protrude. There is a corresponding back plate 83 having a similarly engraved series of radially aligned deceleration nozzles 46 that are aligned with and oppositely oriented to these radially aligned acceleration nozzles 45. These radially aligned deceleration nozzles 46 also project to form a back plate flow path 84 adjacent to the inlet plate flow path 82 and the circular plenum 50. These radially aligned deceleration nozzles 46 have a deceleration orifice 48 with a width of 1.4 mm. The radially aligned acceleration nozzles 45 are separated from the radially aligned deceleration nozzles 46 by a 1.8 mm cylindrical radial multislit aerosol concentrator aerosol separation space 49. The circular plenum 50 is adjacent to two convergent discharge channels 85 on both sides of the cylindrical radial multislit aerosol concentrator 24, which terminates at the cylindrical radial multislit aerosol concentrator outlet 51, and is cylindrical. The radial multi-slit aerosol concentrator outlet 51 has a medical connection taper to facilitate fixation of the filter to the cylindrical radial multi-slit aerosol concentrator outlet 51. In this configuration, the primary intermediate dry powder aerosol 14 transferred through the cylindrical evaporation chamber 6 enters the radially aligned acceleration nozzles 45, resulting in the particles in the primary intermediate dry powder aerosol 14 being accelerated slit orifice. Cylindrical radial multi-slit aerosol concentrator between 47 and deceleration slit orifice 48 Velocity to have momentum to enter a deceleration nozzle 46 radially aligned as a secondary intermediate dry powder aerosol 17 across the aerosol separation space 49. Will increase. A small amount of aerosol exits through the cylindrical radial multislit aerosol concentrator aerosol separation space 49 at right angles to the flow of the primary intermediate dry powder aerosol 14 to form the secondary discharge aerosol 86. The secondary discharge aerosol 86 flows through the inlet plate flow path 82 and the back plate flow path 84 into the circular plenum 50, from which it flows into the two convergent discharge channels 85, and then through the cylindrical radial multislit aerosol concentrator outlet. Exit through 51. When the primary intermediate dry powder aerosol 14 passes through the deceleration nozzles 46 arranged radially, the speed decreases, and the secondary intermediate dry powder aerosol 17 has a secondary intermediate dry powder aerosol volume flow rate 93 and a secondary intermediate dry powder aerosol particle concentration 94. The secondary intermediate dry powder aerosol 17 then flows through the output end 26 (FIG. 6C) of the cylindrical radial multislit aerosol concentrator. The secondary intermediate dry powder aerosol volume flow rate 93 is controlled by an output device connected to the recovery cone 79.

The fourth configuration of the present invention includes a liquid aerosol generation nozzle 3, a countercurrent tube 54, a flow distributor 5, a cylindrical evaporation chamber 6, a cylindrical radial multi-slit aerosol concentrator 24, and a cylindrical linear single-slit aerosol concentrator 9. An aerosol generation system comprising a two-stage concentrator 96, shown in FIGS. 7A-7D. In this configuration, the secondary intermediate dry powder aerosol 17 is in the convergent cylindrical linear single-slit aerosol concentrator input path 19 of the cylindrical linear single-slit aerosol concentrator 9 from the cylindrical radial multi-slit aerosol concentrator output end 26. Flow to. The secondary intermediate dry powder aerosol 17 is a cylindrical linear single slit aerosol in the same manner that the primary intermediate dry powder aerosol 14 in the second configuration is treated by the cylindrical linear single slit aerosol concentrator 9. Processed by the concentrator 9. The inhalable dry powder aerosol 15 flows into the recovery cone 79 through the divergent cylindrical linear single-slit aerosol concentrator output path 22. A device connected to this cone controls the inhalable dry powder aerosol volume flow rate 91 of the inhalable dry powder aerosol 15. In this two-stage configuration, the distribution of flow through the two-stage concentrator 96 is controlled by controlling the inhalable dry powder aerosol volume flow rate 91 of the cylindrical linear single slit aerosol concentrator 9.

<Example>
The following data was generated using the present invention in which the aerosol processing system was operated horizontally on its control tabletop.

To assess the performance of the present invention, polyvinylpyrrolidone (PVP), a polymeric excipient available in a wide range of molecular weights, was used at various concentrations. PVP was used as an alternative to both surfactants and other agents that form solutions and suspensions within the viscosity range to be considered. A surfactant suspension containing phospholipids contained in Minisurf provided by Molecular Express was used. Particle size was measured with a Maple Miller cascade impactor and indicated by aerodynamic central particle size (MMAD). The heliox used in these experiments was 80% helium and 20% oxygen.

The effect of heliox-based aerosol production and treatment on particle size compared to air was evaluated in the third configuration of the invention, which incorporates a cylindrical radial multislit aerosol concentrator into the invention.

To evaluate the influence of the pressure of the gas, with a 10% 8kDa PVP, KB _- using a nozzle that N-500 and KB-N-600, to generate the particles in 1 ml / min. The volumetric flow rate of the primary intermediate dry powder aerosol was set in the range of 160 to 200 l / min. The volumetric flow rate of inhalable dry powder aerosol was controlled to 30 l / min. The output (MMAD) of the present invention when the radial slit concentrator was used was significantly reduced as compared with air when heliox was used as the gas for aerosol formation and treatment (FIGS. 9 and 10). The particle size decreased as the compressed gas pressure (CGP) increased (Fig. 9).

To assess the effect of aerosolization rate on particle size with air and heliox, from 9.33% surfactorant suspension and 10% 8 kDa PVP solution, 40 psi compressed air / helicopter using a nozzle named KB-N-500. Aerosols were produced at ox pressure. At all aerosolization rates (AR) between 0.5 ml / min and 3 ml / min, the MMAD of aerosols produced and processed with Heliox was less than 3 μm in both PVP solutions and surfactant suspensions. (Fig. 10). When the surfactant is aerosolized, the particle size appears to be largely independent of the flow rate when the flow rate is in the range of 1 ml / min to 3 ml / min. The geometric standard deviation ρg was in the range of 1.7 to 2.2 for air, but was in the range of 1.9 to 2.7 for Heliox.

Since the viscosity of the surfactant suspension increases sharply as the concentration of the surfactant increases, the effect of the viscosity of the liquid on the particle size was evaluated using Heliox as the gas for aerosol formation and treatment. The viscosities of 10% and 20% solutions of PVP with nominal molecular weights of 8, 29, 40 and 58 kDa were measured with a capillary rheometer and indicated by cSt. The Ohnesorge number Oh is proportional to the liquid kinematic viscosity. At high Oh (Oh> 0.01), the increase in damping due to the viscous force of the liquid suppresses liquid deformation and liquid splitting. Aerosolizing the PVP solution at 1 ml / min at a compressed heliox pressure of 40 psi using a nozzle called KB-N-700, the viscosity (μ _f ) between 4 cSt and 39 cSt is slightly higher at higher viscosities. The particle size (MMAD) has increased (Fig. 11). Although not included in FIG. 11, the viscosity of the fluid is not limited to less than 39 cSt and may reach 100 cSt. Notably, the maximum viscosity of the solution aerosolized by the mesh nebulizer is less than 4 cSt. Therefore, the present invention significantly expands the range of molecular size and solution viscosity at which fine particle aerosols can be immediately produced and fed.

To investigate the efficiency of aerosol particle output by air and heliox using a cylindrical radial multi-slit aerosol concentrator, a 10% PVP solution and a 9.33% surfactant suspension were used with a nozzle named KB-N-500 for 40 psi. It was made into an aerosol at 44 l / min and recovered at an inhalable dry powder aerosol volume flow rate. From Table 1, it can be seen that the output of 10% PVP increases to 192 mg / min at 3 ml / min. With Heliox, the output increased slightly to 198 mg / min, despite the expected reduction in particle size. When Heliox was used as the aerosolizing gas, the output efficiency of surfactant and the output efficiency of PVP were basically the same.

To show that it is possible to treat large particle agglomerates using a cylindrical radial multi-slit aerosol concentrator, 10 ml and 20 ml of 10% 8 kDa PVP solution was added to the KB at a aerosolization rate of 3 ml / min. It was aerosolized at a compressed air pressure of 40 psi using a nozzle called -N-500. Output masses of 0.7 g and 1.2 g were recovered at 3.3 min and 6.7 min, respectively. These data indicate that the invention can potentially deliver surfactants and other molecules at doses suitable for clinical use.

In the second configuration of the present invention, the effect of CGP on MMAD, the effect of increased aerosolization rate on dosing rate (DR), and inhalable dry powder aerosol volume flow rate (RAVF) are the output mass concentrations of the aerosol treatment system. Cylindrical radial multi-slit aerosol concentrators have been replaced by single-slit aerosol concentrators to assess their impact on (MC) and output efficiency (OE). In these experiments, the volumetric flow rate of the primary intermediate dry powder aerosol was 160-200 l / min and the volumetric flow rate of the inhalable dry powder aerosol was 12-44 l / min.

To aerosolize the 10% 8 kDa PVP solution and the 8.85% surfactant suspension, an aerosol was produced using Heliox and a nozzle named KB-N-500 at an aerosolization rate of 3 ml / min. In both cases, MMAD decreased as CGP increased (Fig. 12). For comparison, the particle size of the aerosol produced from a 10% 8 kDa PVP solution at 40 psi with air at the same nozzle and at the same aerosolization rate was 4.1 μm.

When a single-slit aerosol concentrator was used with Heliox at a volumetric flow rate of 44 l / min inhalable dry powder aerosol, up to 258 mg / min of PVP particles were delivered with an efficiency of up to 86% (FIG. 13). At an aerosolization rate of 1 ml / min, the output mass concentration of the surfactant was 78 mg / min (efficiency 84%), and at an aerosolization rate of 3 ml / min, the output mass concentration was 207 mg / min. Therefore, the use of Heliox with a cylindrical linear single-slit aerosol concentrator significantly improved the aerosol concentration compared to that obtained with a cylindrical radial multi-slit aerosol concentrator (Table 1). ..

10 ml and 30 ml of 10% 8 kDa PVP at 3 ml / min using a nozzle called KB-N-500 to show that large particle agglomerates can be treated with a single slit aerosol concentrator. And was aerosolized at a compression heliox pressure of 40 psi. At output, 0.86 g and 2.2 g output masses were recovered at 3.3 min and 10 min, respectively.

These data have the potential for the present invention to provide particles <3 μm MMAD at 3 mg / s for every single breath and output a total dose of ~ 2 g of surfactant in ~ 10 minutes. It is shown that. When a cylindrical linear single-slit aerosol concentrator was used, aerosol deposition on the orifice was minimal. The cylindrical linear single-slit aerosol concentrator had the least amount of aerosol loss on the wall, and the divergent output path had the most wall deposition. At these very high particle concentrations, this particle-wall interaction at the divergent output path is the performance of the concentrator within the particle size, particle concentration and total processing mass reported herein. It seems that it did not affect. Therefore, using a cylindrical linear single-slit aerosol concentrator with Heliox has made it possible to concentrate a higher total particle mass than using a cylindrical radial multi-slit concentrator.

A third configuration using a cylindrical radial multi-slit aerosol concentrator to achieve high particle concentration, and a cylindrical radial multi-slit aerosol concentrator and a cylindrical linear single-slit aerosol concentrator to form a two-stage concentrator. The relative usefulness of the fourth configuration with a series combination of vessels was evaluated by the ratio of the primary intermediate dry powder aerosol volume flow to the high inhalable dry powder aerosol volume flow. A volumetric flow rate of inhalable dry powder aerosol was selected at 12 l / min.

The third configuration using a cylindrical radial multi-slit aerosol concentrator was evaluated using air as the aerosol-producing gas and the diluent gas. When using a nozzle called KB-N-400 and using 10% 8 kDa PVP of a liquid flow rate of 1 ml / min with a volumetric flow rate of 80 l / min primary intermediate dry powder aerosol, the output mass concentration is 2.2 mg / l and the output. The efficiency was 26% and the estimated MMAD was 3.3 μm. The output pressure was 0.4 water column cm. When the total volumetric flow rate of the primary intermediate dry powder aerosol was increased to 160 l / min, the mass concentration was 1.5 mg / l and the output efficiency was less than 20%. Of particular note is the use of a KB-N-400 nozzle with a cylindrical linear single-slit aerosol concentrator to generate aerosols from 5% 8 kDa PVP with a total flow rate of 60 ml / min and an aerosolization rate of 0.5 ml / min. At that time, a mass concentration of 0.9 mg / l was achieved. The pressure at the output was 6 water columns cm. The MMAD was estimated to be about 2.9 μm.

A fourth configuration with a two-stage concentrator was evaluated using air. The case where the volumetric flow rate of the primary intermediate dry powder aerosol of air was 160 l / min and the volumetric flow rate of the inhalable dry powder aerosol was limited to 12 l / min was evaluated. In this case, if the aerosolization rate of 10% 8 kDa PVP is 3 ml / min using a nozzle called KB-N-500, the mass concentration will be 9.3 mg / l, and the output efficiency of the entire two-stage concentrator will be 37%. became. The output pressure was 1.5 water column cm. The MMAD was about 3.2 μm.

In addition, when Heliox is used as the processing gas in the second configuration with a nozzle called KB-N-500 and a cylindrical linear single-slit aerosol concentrator, the volumetric flow rate of the primary intermediate dry powder aerosol is 160 to 200 l / min. Assuming that the volumetric flow rate of the inhalable dry powder aerosol was limited to 12 l / min and the aerosolization rate was 3 ml / min, the output mass concentration was 14.5 mg / l and the output efficiency was 58% (Fig. 14). The output pressure was just 15 water columns cm. The MMAD was about 2.9 μm.

Taken together, these data show that it is advantageous to use a two-stage concentrator when using air to produce high concentrations of aerosols. Notably, the efficiency and power of single-stage cylindrical linear single-slit aerosol concentrators, when Heliox can be used, is overwhelmingly high, especially when 2-3 μm MMAD aerosols are produced. ..

The split gas stream in the fourth configuration with a two-stage concentrator was evaluated with air or heliox without aerosolization. In this mode, when operating with air at a primary intermediate dry powder volume flow rate of 160 l / min, the ratio of the primary intermediate dry powder aerosol volume flow rate to the secondary intermediate dry powder volume flow rate is a cylindrical radial multislit aerosol. It was estimated to be 2.7 in the concentrator. The ratio of the secondary intermediate dry powder volume flow rate to the inhalable dry powder volume flow rate was estimated to be 4.9 for the cylindrical linear single slit aerosol concentrator. When this two-stage configuration is operated using a heliox with a primary intermediate dry powder aerosol volume flow rate of 210 l / min and an inhalable dry powder aerosol volume flow rate limited to 12 l / min, the input to the output gas flow The gas flow rate was 4.9 for the first-stage cylindrical radial multi-slit aerosol concentrator and 3.6 for the cylindrical linear single-slit aerosol concentrator, with an overall efficiency of 41% for the two-stage concentrator. .. The output pressure was 0.6 cm. This demonstrates the versatility and practicality of this two-stage concentrator.

Assuming that spherical particles were generated with an ideal lognormal distribution, the number of PVP / surfactant particles per liter of heliox in an aerosol _{with a diameter of 2.6 μm (σ g = 1.9) is a theory developed by Hatch and Choate.} Based on this, it was calculated as ^{9.8 × 10 9 at 14.5 mg / l.} Based on the approach by Smolychowski, the number of particles is then reduced by 0.06% after 0.2 seconds due to coagulation. Therefore, at these concentrations, the effect of coagulation can be ignored in the present invention.

The surface tension of surfactant before and after aerosolization by SUPRAER was measured by the Contact Angle Analyzer (FTA-200) using the pendant drop shape method. The static surface tensions of 4 mg / ml surfactant before and after aerosolization according to the present invention were 22.2 mN / m and 22.6 mN / m, respectively. There was no decrease in the surface tension of the surfactant due to the aerosolization treatment and the resuspension treatment.

<Use of Examples of the Present Invention>
These data show the excellent efficiency of this configuration of the present invention when administering large doses of particulate aerosols with a geometric standard deviation of 1.6-2.7 at 1.5-4 μm MMAD. The present invention can meet the needs of aerosol delivery in adults, children and toddlers. The present invention is also suitable for extremely rapid emergency delivery of therapeutic aerosols in other life-threatening situations.

Through the use of a cylindrical linear single-slit aerosol concentrator in combination with the use of Heliox, an aerosol with an aerodynamic central particle size (MMAD) of less than 3 μm is produced from a 9.33% surfactant suspension (viscosity: 34 cP). The capacity is achieved and a high payload dry powder aerosol containing up to 3 mg / s of pure phospholipids is delivered with an efficiency of 69% to 84%. The low surface tension properties of surfactant are maintained even after aerosolization and resuspension. The present invention may be able to deliver a constant 3 mg / s through each and all inhalations without interruption over the entire treatment time. Surfactant dosing rates and total doses are 10 to 20 times higher than the rates and doses achievable with competing devices. For the first time in a variety of treatments for adults with impaired lung function, doses of aerosolized surfactant suitable for clinical use will be achievable. Therefore, the present invention may provide life-saving physiologic benefits to enable elimination of the pulmonary inflammatory process, along with surfactants containing SPB proteins (or mimetics).

According to the present invention, heliox produces and delivers surfactant aerosols more efficiently than air. In addition, Heliox facilitates the penetration of aerosols deeper into the lungs and improves gas exchange, especially in patients with pulmonary dysfunction. The physical properties of Heliox are that the delivery of aerosols less than 3 μm MMAD using a cylindrical linear single-slit aerosol concentrator was up to 86%, compared to 69% efficiency in the case of air. It has become possible to do it efficiently. This lower loss made it possible to achieve higher total feed doses of surfactant. In addition, Heliox has a higher thermal conductivity and specific heat than air, facilitating the process of evaporating water from the aerosol. This has made it possible to deliver surfactant with high efficiency even at high doses. Cylindrical linear single-slit aerosol concentrators are used with air rather than heliox at these flow rates (primary intermediate dry powder aerosol volume flow: 160-200 l / min, inhalable dry powder aerosol volume flow: 44 l / min). In this case, the feed pressure to the patient is higher than 38 water column cm, but with the aerosol, this pressure is only 13 water column cm. High aerosol delivery pressure when air is used with a cylindrical linear single slit aerosol concentrator is not only unfavorable for patients who breathe spontaneously, but it also results in continuous positive airway pressure when used in intensive care unit equipment. A lower limit is set that is too high for ventilation at (CPAP) or positive end-expiratory pressure (PEEP). Cylindrical radial multi-slit aerosol concentrators, when used with air, have a low aerosol feed pressure of 3 centimeters and an efficiency between 59% and 64%. To provide a unit that meets the needs of clinical facilities that are free of heliox or choose not to use heliox, according to the invention described above, for some of the embodiments described, aerosol-producing gases And it was possible to use air or heliox as the aerosol treatment gas.

Further embodiments 1-141 of the present invention are described below.

1. 1. Inhalable Dry Powder Aerosol A aerosol generation system for producing inhalable dry powder aerosol 15 from a solution or suspension at a volumetric flow rate of 91.
It has a nozzle input end 11 designed to receive a solution or suspension, a nozzle gas supply 55 designed to receive the nozzle gas 2, and further outputs a liquid aerosol 13 suspended in the nozzle gas 2. A liquid aerosol generation nozzle 3 having a nozzle output end 36 and
A cylindrical evaporation chamber input end 7 connected to a nozzle input end 36 and a dilution gas supply unit 60 to receive both the liquid aerosol 13 and the dilution gas 4 suspended in the nozzle gas 2 and a primary intermediate dry powder aerosol 14 are primary. A cylindrical evaporation chamber 6 having an intermediate dry powder aerosol volume flow of 89 and a cylindrical evaporation chamber outflow end 8 that outputs at a primary intermediate dry powder aerosol particle concentration of 90.
Cylindrical Linear Single Slit Aerosol Concentrator 9 A cylindrical linear single slit aerosol concentrator 9 having a cylindrical linear single slit aerosol concentrator 9 connected to an output end 8 of a cylindrical evaporation chamber. Convergence from the cylindrical linear single-slit aerosol concentrator input end 10 toward the cylindrical linear single-slit aerosol concentrator input orifice 20 connected to the cylindrical linear single-slit aerosol concentrator aerosol separation space 40. The cylindrical linear single-slit aerosol concentrator input path 19 is provided, and the cylindrical linear single-slit aerosol concentrator aerosol separation space 40 is a cylindrical linear single-slit aerosol concentrator outlet 44 and a cylindrical linear single-slit aerosol. Cylindrical linear single-slit aerosol concentrator output orifice 21 connected to both of the concentrator output orifice 21 has a suckable dry powder aerosol volume flow rate 91 lower than the primary intermediate dry powder aerosol volume flow rate 89 and a primary intermediate dry powder. Inhalable dry powder with an aerosol particle concentration of 90 or more Inhalable dry powder with an aerosol particle concentration of 92 A divergent cylindrical linear single slit that outputs an aerosol 15 Cylindrical linear single slit connected to an aerosol concentrator output path 22 Aerosol concentrator 9 and
Aerosol generation system.

2. At least one of the nozzle gas 2 and the diluent gas 4 is a heliox.
The aerosol generation system according to the first embodiment.

3. 3. At least one of the nozzle gas 2 and the diluent gas 4 is air.
The aerosol generation system according to the first embodiment.

4. The primary intermediate dry powder aerosol volume flow rate 89 is between 80 l / min and 200 l / min,
An aerosol generation system according to any one of Examples 1 to 3 described above.

5. The cylindrical linear single-slit aerosol concentrator output orifice 21 is between 1 cm and 5 cm in length and between 1 mm and 2 mm in width.
The aerosol generation system according to any one of Examples 1 to 4 described above.

6. The solution or suspension contains a surfactant,
An aerosol generation system according to any one of Examples 1 to 5 described above.

7. The cylindrical linear single-slit aerosol concentrator 9 has a width of less than 2 mm and extends between the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21. Cylindrical linear single slit aerosol concentrator with aerosol separation space 40,
The aerosol generation system according to any one of Examples 1 to 6 described above.

8. The convergent cylindrical single-slit aerosol concentrator input path 19 is from 10 degrees from the cylindrical linear single-slit aerosol concentrator input end 10 toward the center of the cylindrical linear single-slit aerosol concentrator input orifice 20. Convergence between 60 degrees Cylindrical linear single slit aerosol concentrator Converges at input path angle 52,
An aerosol generation system according to any one of Examples 1 to 7 described above.

9. The divergent cylindrical single-slit aerosol concentrator output path 22 is a divergent cylindrical single-slit aerosol concentrator output between 10 and 60 degrees from the cylindrical linear single-slit aerosol concentrator output orifice 21. It diverges at a road angle of 53,
The aerosol generation system according to any one of Examples 1 to 8 described above.

10. Cylindrical Linear Single Slit Aerosol Concentrator An engraving plenum 43 that connects the aerosol separation space 40 and the cylindrical linear single slit aerosol concentrator outlet 44, with an engraving plenum volume between 30 ml and 300 ml. 43 more
An aerosol generation system according to any one of Examples 1 to 9 described above.

11. Cylindrical linear single slit aerosol concentrator outlet 44 has a diameter of 10 to 20 mm,
An aerosol generation system according to any one of Examples 1 to 10 described above.

12. When in use, the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21 extend substantially in the vertical direction.
An aerosol generation system according to any one of Examples 1 to 11 described above.

13. The aerosol production system is designed to output a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
An aerosol generation system according to any one of Examples 1 to 12 described above.

14. Aerosol production systems are designed to aerosolize solutions or suspensions with solution or suspension viscosities of 4 to 39 cSt.
An aerosol generation system according to any one of Examples 1 to 13 described above.

15. The nozzle gas 2 has a nozzle gas pressure between 207 kPa and 414 kPa.
An aerosol generation system according to any one of Examples 1 to 14 described above.

16. The inhalable dry powder aerosol 15 has an inhalable dry powder aerosol pressure of less than 1 water column cm.
The aerosol generation system according to the second embodiment.

17. The inhalable dry powder aerosol 15 has an inhalable dry powder aerosol pressure of less than 2 water columns cm.
The aerosol generation system according to the third embodiment.

18. Inhalable dry powder aerosol volume flow rate 91 is 10-15 l / min, concentration efficiency is higher than 30%,
An aerosol generation system according to any one of Examples 1 to 17 described above.

19. The aerosol generation system has no flow control device at the cylindrical linear single-slit aerosol concentrator outlet 44 of the cylindrical linear single-slit aerosol concentrator 9.
An aerosol generation system according to any one of Examples 1 to 18 described above.

20. Further comprising a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 95.
An aerosol generation system according to any one of Examples 1 to 19 described above.

21. Aerosol production systems receive solutions or suspensions at a solution volume flow or suspension volume flow of 0.1 to 3 ml / min and a dry powder aerosol aerodynamic center particle of 3 μm or less at a drug mass flow of at least 150 mg / min. Designed to deliver the drug in the form of solid particles with a diameter (MMAD),
The aerosol generation system according to any one of Examples 1 to 20 described above.

22. Aerosol production systems are designed to receive solutions or suspensions with solution viscosities or suspension viscosities greater than 4 cSt.
The aerosol generation system according to Example 21.

23. The aerosol production system outputs an inhalable dry powder aerosol volumetric flow rate of 91 between 12 l / min and 44 l / min, thereby delivering the drug at a drug mass concentration of at least 5 mg / l and up to 14.5 mg / l. Designed to
The aerosol generation system according to Example 22.

24. Inhalable dry powder aerosol A method for producing inhalable dry powder aerosol 15 from a solution or suspension at a volumetric flow rate of 91.
A solution or suspension and nozzle gas 2 are supplied to the liquid aerosol generation nozzle 3 to supply the solution or suspension.
The liquid aerosol 13 suspended in the nozzle gas 2 is output from the liquid aerosol generation nozzle 3 to the cylindrical evaporation chamber 6.
The diluent gas 4 is supplied to the cylindrical evaporation chamber 6 to supply the diluted gas 4.
From the cylindrical evaporation chamber 6, a primary intermediate dry powder aerosol 14 having fine dry powder particles suspended in a gas, which allows inhalation of particles containing medically effective agents, is provided with a primary intermediate dry powder aerosol volume flow 89 and a primary. Output at an intermediate dry powder aerosol particle concentration of 90,
The primary intermediate dry powder aerosol 14 is supplied to the cylindrical linear single-slit aerosol concentrator 9, and the cylindrical linear single-slit aerosol concentrator 9 converges toward the cylindrical linear single-slit aerosol concentrator input orifice 20. Convergent cylindrical single-slit aerosol concentrator input path 19 and divergent cylindrical single-slit aerosol concentrator output path 22 diverging from the cylindrical linear single-slit aerosol concentrator output orifice 21.
The inhalable dry powder aerosol 15 is output at a primary intermediate dry powder aerosol volume flow rate of less than 89 and an inhalable dry powder aerosol particle concentration 92 higher than the primary intermediate dry powder aerosol particle concentration 90.
Method.

25. Further comprising supplying heliox as at least one of the nozzle gas 2 and the diluent gas 4.
The method according to Example 24.

26. Further comprising supplying air as at least one of the nozzle gas 2 and the diluent gas 4.
The method according to Example 24.

27. Further comprising producing at a primary intermediate dry powder aerosol volume flow rate of 89 between 80 l / min and 200 l / min,
The method according to any one of Examples 24 to 26 described above.

28. Cylindrical linear single-slit aerosol concentrator output orifice 21 further comprises a length between 1 cm and 5 cm and a width between 1 mm and 2 mm.
The method according to any one of Examples 24 to 27 described above.

29. Further comprising adding a surfactant as a component of the solution or suspension,
The method according to any one of Examples 24 to 28 described above.

30. The cylindrical linear single-slit aerosol concentrator 9 has a width of less than 2 mm and extends between the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21. Cylindrical linear single slit aerosol concentrator further comprising providing an aerosol separation space 40.
The method according to any one of Examples 24 to 29 described above.

31. Convergent cylindrical single-slit aerosol concentrator input path 19 from 10 degrees from the cylindrical linear single-slit aerosol concentrator input end 10 toward the center of the cylindrical linear single-slit aerosol concentrator input orifice 20. Convergent Cylindrical Linear Single Slit Aerosol Concentrator Between 60 Degrees Further Includes Provision to Converge at Input Path Angle 52.
The method according to any one of Examples 24 to 30 described above.

32. Divergent Cylindrical Single Slit Aerosol Concentrator Output Path 22 from Cylindrical Linear Single Slit Aerosol Concentrator Output Orifice 21 to Divergent Cylindrical Single Slit Aerosol Concentrator Output Between 10 and 60 Degrees Further including providing so as to diverge at a road angle 53,
The method according to any one of Examples 24 to 31 described above.

33. Cylindrical Linear Single Slit Aerosol Concentrator An engraving plenum 43 that connects the aerosol separation space 40 and the cylindrical linear single slit aerosol concentrator outlet 44, with an engraving plenum volume between 30 ml and 300 ml. Further including providing 43,
The method according to any one of Examples 24 to 32 described above.

34. Further including the diameter of the cylindrical linear single slit aerosol concentrator outlet 44 being 10 to 20 mm.
The method according to any one of Examples 24 to 33 described above.

35. Further comprising arranging the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21 so that they extend substantially in the vertical direction.
The method according to any one of Examples 24 to 34 described above.

36. Further comprising outputting a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
The method according to any one of Examples 24 to 35 described above.

37. Further comprising aerosolizing a solution or suspension having a solution viscosity or suspension viscosity of 4 to 39 cSt.
The method according to any one of Examples 24 to 36 described above.

38. Further comprising supplying the nozzle gas 2 with a nozzle gas 2 pressure between 207 kPa and 414 kPa,
The method according to any one of Examples 24 to 37 described above.

39. Further comprising producing inhalable dry powder aerosol 15 at an inhalable dry powder aerosol pressure of less than 1 water column.
The method according to Example 25.

40. Further comprising producing inhalable dry powder aerosol 1 at an inhalable dry powder aerosol pressure of less than 2 water columns.
The method according to Example 26.

It further comprises producing with an inhalable dry powder aerosol volume flow rate of 91 at 10-15 l / min with a concentration efficiency greater than 41.30%.
The method according to any one of Examples 24 to 40 described above.

42. The aerosol generation system further comprises omitting any flow control device at the linear single slit aerosol concentrator outlet 44 of the cylindrical linear single slit aerosol concentrator 9.
The method according to any one of Examples 24 to 41 described above.

43. Further comprising providing a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 79.
The method according to any one of Examples 24 to 42 described above.

44. Dry powder aerosol with aerodynamic center particle size of 3 μm or less at a solution volume flow rate or suspension volume flow rate of 0.1 to 3 ml / min and a drug mass flow rate of at least 150 mg / min. Further comprising delivering the drug in the form of solid particles with MMAD),
The method according to any one of Examples 24 to 43 described above.

Further comprising supplying a solution or suspension with a solution viscosity or suspension viscosity greater than 45.4 cSt,
The method according to Example 44.

46. The method outputs an inhalable dry powder aerosol volume flow rate 91 between 12 l / min and 44 l / min, thereby delivering the drug at a drug mass concentration of at least 5 mg / l and at most 14.5 mg / l. Designed,
The method according to Example 45.

47. Further comprising controlling the volume flow rate ratio such that the ratio of the primary intermediate dry powder aerosol volume flow rate 89 to the inhalable dry powder volume flow rate 91 is less than 5.
The method according to any one of Examples 24 to 46 described above.

48. Inhalable Dry Powder Aerosol A aerosol generation system for producing inhalable dry powder aerosol 15 from a solution or suspension at a volumetric flow rate of 91.
It has a nozzle input end 11 designed to receive a solution or suspension, a nozzle gas supply 55 designed to receive the nozzle gas 2, and further outputs a liquid aerosol 13 suspended in the nozzle gas 2. A liquid aerosol generation nozzle 3 having a nozzle output end 36 and
The cylindrical evaporation chamber input end 7 connected to the nozzle input end 36 and the dilution gas supply unit 60 to receive both the liquid aerosol 13 and the dilution gas 4 suspended in the nozzle gas 2 and the primary intermediate dry powder aerosol 14 are in the primary intermediate. A cylindrical evaporation chamber 6 having a dry powder aerosol volume flow of 89 and a cylindrical evaporation chamber output end 8 that outputs at a primary intermediate dry powder aerosol particle concentration of 90.
A cylindrical radial multi-slit aerosol concentrator 24 that extends from a position at or near the center of the cylindrical radial multi-slit aerosol concentrator 24 to a position further away from the center of the cylindrical radial multi-slit aerosol concentrator 24. Cylindrical radial multi-slit aerosol concentrator input end 25 with three slits and connected to the output end 8 of the cylindrical evaporation chamber, and secondary intermediate dry powder aerosol 17 secondary intermediate dry powder aerosol volume flow 93 and secondary It has a cylindrical radial multi-slit aerosol concentrator output end 26 that outputs at an intermediate dry powder aerosol particle concentration 94, and the secondary intermediate dry powder aerosol volume flow rate 93 is less than the primary intermediate dry powder aerosol volume flow rate 89, and is secondary intermediate drying. The cylindrical radial multi-slit aerosol concentrator 24, which has a powder aerosol particle concentration 94 higher than the primary intermediate dry powder aerosol particle concentration 90, and
Cylindrical Radial Multi-Slit Aerosol Concentrator A cylindrical linear single-slit aerosol concentrator 9 having a cylindrical linear single-slit aerosol concentrator input end 10 connected to an output end 26, the cylindrical linear single-slit aerosol concentrator 9. The concentrator 9 is directed from the cylindrical linear single-slit aerosol concentrator input end 10 toward the cylindrical linear single-slit aerosol concentrator input orifice 20 connected to the cylindrical linear single-slit aerosol concentrator aerosol separation space 40. Convergent cylindrical single-slit aerosol concentrator input path 19 is provided, and the cylindrical linear single-slit aerosol concentrator aerosol separation space 40 is a cylindrical linear single-slit aerosol concentrator outlet 44 and a cylindrical wire. Cylindrical linear single-slit aerosol concentrator output orifice 21 connected to both of the state single-slit aerosol concentrator output orifice 21 is a suckable dry powder aerosol volume flow rate 91 lower than the secondary intermediate dry powder aerosol volume flow rate 93. It is connected to a divergent cylindrical linear single-slit aerosol concentrator output path 22 that outputs a dry powder aerosol 15 that can be sucked at a dry powder aerosol particle concentration 92 that is higher than the secondary intermediate dry powder aerosol particle concentration 94. Cylindrical linear single slit aerosol concentrator 9 and
Aerosol generation system.

49. At least one of the nozzle gas 2 and the diluent gas 4 is a heliox.
The aerosol generation system according to Example 48.

50. At least one of the nozzle gas 2 and the diluent gas 4 is air.
The aerosol generation system according to Example 48.

51. The primary intermediate dry powder aerosol volume flow rate 89 is between 80 l / min and 200 l / min,
An aerosol generation system according to any one of Examples 48 to 50 described above.

52. The cylindrical linear single slit aerosol concentrator output orifice 21 is between 1 cm and 5 cm in length and between 1 mm and 2 mm in width.
An aerosol generation system according to any one of Examples 48 to 51 described above.

53. The solution or suspension contains a surfactant,
An aerosol generation system according to any one of Examples 48 to 52 described above.

54. The cylindrical linear single-slit aerosol concentrator 9 has a width of less than 2 mm and extends between the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21. Cylindrical linear single slit aerosol concentrator with aerosol separation space 40,
An aerosol generation system according to any one of Examples 48 to 53 described above.

55. The convergent cylindrical single-slit aerosol concentrator input path 19 is from 10 degrees from the cylindrical linear single-slit aerosol concentrator input end 10 toward the center of the cylindrical linear single-slit aerosol concentrator input orifice 20. Convergence between 60 degrees Cylindrical linear single slit aerosol concentrator Converges at input path angle 52,
An aerosol generation system according to any one of Examples 48 to 54 described above.

56. The divergent cylindrical single-slit aerosol concentrator output path 22 is a divergent cylindrical single-slit aerosol concentrator output between 10 and 60 degrees from the cylindrical linear single-slit aerosol concentrator output orifice 21. It diverges at a road angle of 53,
An aerosol generation system according to any one of Examples 48 to 55 described above.

57. Cylindrical Linear Single Slit Aerosol Concentrator An engraving plenum 43 that connects the aerosol separation space 40 and the cylindrical linear single slit aerosol concentrator outlet 44, with an engraving plenum volume between 30 ml and 300 ml. 43 more
An aerosol generation system according to any one of Examples 48 to 56 described above.

58. Cylindrical linear single slit aerosol concentrator outlet 44 has a diameter of 10 to 20 mm,
An aerosol generation system according to any one of Examples 48 to 57 described above.

59. When in use, the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21 extend substantially in the vertical direction.
An aerosol generation system according to any one of Examples 48 to 58 described above.

60. The aerosol production system is designed to output a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
An aerosol generation system according to any one of Examples 48 to 59 described above.

61. Aerosol production systems are designed to aerosolize solutions or suspensions with solution or suspension viscosities of 4 to 39 cSt.
An aerosol generation system according to any one of Examples 48 to 60 described above.

62. The nozzle gas 2 has a nozzle gas pressure between 207 kPa and 414 kPa.
An aerosol generation system according to any one of Examples 48 to 61 described above.

63. The inhalable dry powder aerosol 15 has an inhalable dry powder aerosol pressure of less than 1 water column cm.
The aerosol generation system according to Example 49.

64. The inhalable dry powder aerosol 15 has an inhalable dry powder aerosol pressure of less than 2 water columns cm.
The aerosol generation system according to Example 50.

65. Cylindrical Radial Multislit Aerosol Concentrator 24 Cylindrical Radial Multislit Aerosol Concentrator Total slit length is at least 4 times the cylindrical linear single slit aerosol concentrator 9 Cylindrical linear single slit aerosol concentrator slit length long,
An aerosol generation system according to any one of Examples 48 to 64 described above.

66. Inhalable dry powder aerosol volume flow rate 91 is 10-15 l / min, concentration efficiency is higher than 30%,
An aerosol generation system according to any one of Examples 48 to 65 described above.

67. The aerosol generation system includes a cylindrical radial multi-slit aerosol concentrator outlet 51 of the cylindrical radial multi-slit aerosol concentrator 24 and a cylindrical linear single-slit aerosol concentrator outlet 44 of the cylindrical linear single-slit aerosol concentrator 9. There is no flow control device in
An aerosol generation system according to any one of Examples 48 to 66 described above.

68. Further comprising a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 95.
An aerosol generation system according to any one of Examples 48 to 67 described above.

69. Aerosol production systems receive solutions or suspensions at a solution volume flow or suspension volume flow of 0.1 to 3 ml / min and a dry powder aerosol aerodynamic center particle of 3 μm or less at a drug mass flow of at least 150 mg / min. Designed to deliver the drug in the form of solid particles with a diameter (MMAD),
An aerosol generation system according to any one of Examples 48 to 68 described above.

70. Aerosol production systems are designed to receive solutions or suspensions with solution viscosities or suspension viscosities greater than 4 cSt.
The aerosol generation system according to Example 69.

71. The aerosol production system outputs an inhalable dry powder aerosol volumetric flow rate of 91 between 12 l / min and 44 l / min, thereby delivering the drug at a drug mass concentration of at least 5 mg / l and up to 14.5 mg / l. Designed to
The aerosol generation system according to Example 70.

72. Inhalable dry powder aerosol A method for producing inhalable dry powder aerosol 15 from a solution or suspension at a volumetric flow rate of 91.
A solution or suspension and nozzle gas 2 are supplied to the liquid aerosol generation nozzle 3 to supply the solution or suspension.
The liquid aerosol 13 suspended in the nozzle gas 2 is output from the liquid aerosol generation nozzle 3 to the cylindrical evaporation chamber 6.
The diluent gas 4 is supplied to the cylindrical evaporation chamber 6 to supply the diluted gas 4.
From the cylindrical evaporation chamber 6, a primary intermediate dry powder aerosol 14 having fine dry powder particles suspended in a gas, which allows inhalation of particles containing medically effective agents, is provided with a primary intermediate dry powder aerosol volume flow 89 and a primary. Output at an intermediate dry powder aerosol particle concentration of 90,
The primary intermediate dry powder aerosol 14 is the center of the cylindrical radial multi-slit aerosol concentrator 24 from the position of the cylindrical radial multi-slit aerosol concentrator 24 at or near the center of the cylindrical radial multi-slit aerosol concentrator 24. Supply into a cylindrical radial multi-slit aerosol concentrator 24 with at least three slits extending further away from
From the cylindrical radial multi-slit aerosol concentrator 24, the secondary intermediate dry powder aerosol 17 is taken from the primary intermediate dry powder aerosol volume flow 89 and above the secondary intermediate dry powder aerosol volume flow 93 and the primary intermediate dry powder aerosol particle concentration 90. Output at a secondary intermediate dry powder aerosol particle concentration of 94,
The secondary intermediate dry powder aerosol 17 is supplied to the cylindrical linear single-slit aerosol concentrator 9, and the cylindrical linear single-slit aerosol concentrator 9 converges toward the cylindrical linear single-slit aerosol concentrator input orifice 20. Convergent cylindrical single-slit aerosol concentrator input path 19 and divergent cylindrical single-slit aerosol concentrator output path 22 diverging from the cylindrical linear single-slit aerosol concentrator output orifice 21.
Secondary intermediate dry powder aerosol Volume flow rate 93 lower than inhalable dry powder aerosol Volume flow rate 91 and secondary intermediate dry powder aerosol particle concentration 94 higher than inhalable dry powder aerosol particle concentration 92 Inhalable dry powder aerosol 15 output do,
Method.

73. Further comprising supplying heliox as at least one of the nozzle gas 2 and the diluent gas 4.
The method according to Example 72.

74. Further comprising supplying air as at least one of the nozzle gas 2 and the diluent gas 4.
The method according to Example 72.

It further comprises producing at a primary intermediate dry powder aerosol volume flow rate of 89 between 75.80 l / min and 200 l / min.
The method according to any one of Examples 72 to 74 described above.

76. Cylindrical linear single-slit aerosol concentrator output orifice 21 further comprises a length between 1 cm and 5 cm and a width between 1 mm and 2 mm.
The method according to any one of Examples 72 to 75 described above.

77. Further comprising adding a surfactant as a component of the solution or suspension,
The method according to any one of Examples 72 to 76 described above.

78. The cylindrical linear single-slit aerosol concentrator 9 has a width of less than 2 mm and extends between the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21. Cylindrical linear single slit aerosol concentrator further comprising providing an aerosol separation space 40.
The method according to any one of Examples 72 to 77 described above.

79. Convergent cylindrical single-slit aerosol concentrator input path 19 from 10 degrees from the cylindrical linear single-slit aerosol concentrator input end 10 toward the center of the cylindrical linear single-slit aerosol concentrator input orifice 20. Convergent Cylindrical Linear Single Slit Aerosol Concentrator Between 60 Degrees Further Includes Provision to Converge at Input Path Angle 52.
The method according to any one of Examples 72 to 78 described above.

80. Divergent Cylindrical Single Slit Aerosol Concentrator Output Path 22 from Cylindrical Linear Single Slit Aerosol Concentrator Output Orifice 21 to Divergent Cylindrical Single Slit Aerosol Concentrator Output Between 10 and 60 Degrees Further including providing so as to diverge at a road angle 53,
The method according to any one of Examples 72 to 79 described above.

81. Cylindrical Linear Single Slit Aerosol Concentrator An engraving plenum 43 that connects the aerosol separation space 40 and the cylindrical linear single slit aerosol concentrator outlet 44, with an engraving plenum volume between 30 ml and 300 ml. Further including providing 43,
The method according to any one of Examples 72 to 80 described above.

82. Further including the diameter of the cylindrical linear single slit aerosol concentrator outlet 44 being 10 to 20 mm.
The method according to any one of Examples 72 to 81 described above.

83. Further comprising arranging the cylindrical linear single-slit aerosol concentrator input orifice 20 and the cylindrical linear single-slit aerosol concentrator output orifice 21 so that they extend substantially in the vertical direction.
The method according to any one of Examples 72 to 82 described above.

84. Further comprising outputting a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
The method according to any one of Examples 72 to 83 described above.

85. Further comprising aerosolizing a solution or suspension having a solution viscosity or suspension viscosity of 4 to 39 cSt.
The method according to any one of Examples 72 to 84 described above.

86. Further comprising supplying the nozzle gas 2 with a nozzle gas 2 pressure between 207 kPa and 414 kPa,
The method according to any one of Examples 72 to 85 described above.

87. Further comprising producing inhalable dry powder aerosol 15 at an inhalable dry powder aerosol pressure of less than 1 water column.
The method according to Example 73.

88. Further comprising producing inhalable dry powder aerosol 15 at an inhalable dry powder aerosol pressure of less than 2 water columns.
The method according to Example 74.

89. The total slit length of the cylindrical radial multi-slit aerosol concentrator 24 of the cylindrical radial multi-slit aerosol concentrator 24 is further included to be at least four times longer than the slit length of the cylindrical linear single-slit aerosol concentrator 9.
The method according to any one of Examples 72 to 88 described above.

Further including producing with an inhalable dry powder aerosol volume flow rate of 91 at 10-15 l / min with a concentration efficiency greater than 90.30%.
The method according to any one of Examples 72 to 89 described above.

91. The aerosol generation system includes a cylindrical radial multi-slit aerosol concentrator outlet 54 of the cylindrical radial multi-slit aerosol concentrator 24 and a cylindrical linear single-slit aerosol concentrator outlet 44 of the cylindrical linear single-slit aerosol concentrator 9. Further including omitting any flow control device in
The method according to any one of Examples 72 to 90 described above.

92. Further comprising providing a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 79.
The method according to any one of Examples 72 to 91 described above.

93. Dry powder aerosol with aerodynamic center particle size of 3 μm or less at a solution volume flow rate or suspension volume flow rate of 0.1 to 3 ml / min and a drug mass flow rate of at least 150 mg / min. Further comprising delivering the drug in the form of solid particles with MMAD),
The method according to any one of Examples 72 to 92 described above.

Further comprising supplying a solution or suspension with a solution viscosity or suspension viscosity greater than 94.4 cSt,
The method according to Example 93.

95. The method outputs an inhalable dry powder aerosol volume flow rate 91 between 12 l / min and 44 l / min, thereby delivering the drug at a drug mass concentration of at least 5 mg / l and at most 14.5 mg / l. Designed,
The method according to Example 94.

96. The ratio of the volume flow rate of the primary intermediate dry powder aerosol to the volume flow rate of the secondary intermediate dry powder 93 and the ratio of the volume flow rate of the secondary intermediate dry powder volume 93 to the volume flow rate of the inhalable dry powder 91 so that both are less than 5. Including further controlling,
The method according to any one of Examples 72 to 95 described above.

97. An aerosol production system for producing an inhalable dry powder aerosol 15 from a solution or suspension.
It has a nozzle input end 11 designed to receive a solution or suspension, a nozzle heliox supply 55 designed to receive a nozzle heliox 2, and a liquid aerosol suspended in the nozzle heliox 2. A liquid aerosol generation nozzle 3 having a nozzle output end 36 for outputting 13 and a nozzle 3
A cylindrical evaporation chamber input end 7 connected to a nozzle input end 36 and a diluted heliox supply unit 60 to receive both the liquid aerosol 13 and the diluted heliox 4 suspended in the nozzle heliox 2, and a primary intermediate dry powder aerosol. A cylindrical evaporation chamber 6 having a cylindrical evaporation chamber output end 8 for outputting 14 at a primary intermediate dry powder aerosol volume flow rate of 89 and a primary intermediate dry powder aerosol particle concentration of 90.
A cylindrical radial multi-slit aerosol concentrator 24 that extends from a position at or near the center of the cylindrical radial multi-slit aerosol concentrator 24 to a position farther from the center of the cylindrical radial multi-slit aerosol concentrator 24. Cylindrical radial multi-slit aerosol concentrator input end 25 with three slits and connected to the output end 8 of the cylindrical evaporation chamber, and an inhalable dry powder aerosol volume flow rate 91 lower than the primary intermediate dry powder aerosol volume flow rate 89. Cylindrical radial multi-slit aerosol concentrator with a cylindrical radial multi-slit aerosol concentrator output end 26 that outputs a dry powder aerosol 15 that can be inhaled at a primary intermediate dry powder aerosol particle concentration of 90 or higher. Vessel 24 and
Aerosol generation system.

98. The primary intermediate dry powder aerosol volume flow rate 89 is between 80 l / min and 200 l / min,
The aerosol generation system according to Example 97.

99. The solution or suspension contains a surfactant,
An aerosol generation system according to any one of Examples 97 to 98 described above.

100. The aerosol production system is designed to output a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
An aerosol generation system according to any one of Examples 97 to 99 described above.

101. Aerosol production systems are designed to aerosolize solutions or suspensions with solution or suspension viscosities of 4 to 39 cSt.
An aerosol generation system according to any one of Examples 97 to 100 described above.

102. Nozzle heliox 2 has a heliox pressure between 207 kPa and 414 kPa,
An aerosol generation system according to any one of Examples 97 to 101 described above.

103. The inhalable dry powder aerosol 15 has an inhalable dry powder aerosol pressure of less than 1 water column cm.
An aerosol generation system according to any one of Examples 97 to 102 described above.

104. Inhalable dry powder aerosol volume flow rate 91 is 10-15 l / min, concentration efficiency is higher than 30%,
An aerosol generation system according to any one of Examples 97 to 103 described above.

105. The aerosol generation system has no flow control device at the cylindrical radial multi-slit aerosol concentrator outlet 51 of the cylindrical radial multi-slit aerosol concentrator 24.
An aerosol generation system according to any one of Examples 97 to 104 described above.

106. Further comprising a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 95.
An aerosol generation system according to any one of Examples 97 to 105 described above.

107. Aerosol production systems receive solutions or suspensions at a solution volume flow or suspension volume flow of 0.1 to 3 ml / min and a dry powder aerosol aerodynamic center particle of 3 μm or less at a drug mass flow of at least 150 mg / min. Designed to deliver the drug in the form of solid particles with a diameter (MMAD),
An aerosol generation system according to any one of Examples 97 to 106 described above.

108. Aerosol production systems are designed to receive solutions or suspensions with solution viscosities or suspension viscosities greater than 4 cSt.
The aerosol generation system according to Example 107.

109. The aerosol production system outputs an inhalable dry powder aerosol volumetric flow rate of 91 between 12 l / min and 44 l / min, thereby delivering the drug at a drug mass concentration of at least 5 mg / l and up to 14.5 mg / l. Designed to
The aerosol generation system according to Example 108.

110. Inhalable system A method of producing an inhalable dry powder aerosol 15 from a solution or suspension at an output volume flow rate of 91.
The solution or suspension and the nozzle heliox 2 are supplied to the liquid aerosol generation nozzle 3 to supply the solution or suspension.
The liquid aerosol 13 floating in the nozzle heliox 2 is output from the liquid aerosol generation nozzle 3 to the cylindrical evaporation chamber 6.
The diluted heliox 4 is supplied to the cylindrical evaporation chamber 6 to supply the diluted heliox 4.
From the cylindrical evaporation chamber 6, a primary intermediate dry powder aerosol 14 having fine dry powder particles suspended in a gas, which allows inhalation of particles containing medically effective agents, is provided with a primary intermediate dry powder aerosol volume flow 89 and a primary. Output at an intermediate dry powder aerosol particle concentration of 90,
The primary intermediate dry powder aerosol 14 is the center of the cylindrical radial multi-slit aerosol concentrator 24 from the position of the cylindrical radial multi-slit aerosol concentrator 24 at or near the center of the cylindrical radial multi-slit aerosol concentrator 24. Supply into a cylindrical radial multi-slit aerosol concentrator 24 with at least three slits extending further away from
The inhalable dry powder aerosol 15 is output at a primary intermediate dry powder aerosol volume flow rate lower than 14 and an inhalable dry powder aerosol particle concentration 92 higher than the primary intermediate dry powder aerosol particle concentration 90.
Method.

111. Further comprises producing at a primary intermediate dry powder aerosol volume flow rate of 89 between 80 l / min and 200 l / min.
The method according to Example 110.

112. Further comprising adding a surfactant as a component of the solution or suspension,
The method according to any one of Examples 110 to 111 described above.

113. Further comprising outputting a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
The method according to any one of Examples 110 to 112 described above.

114. Further comprising aerosolizing a solution or suspension having a solution viscosity or suspension viscosity of 4 to 39 cSt.
The method according to any one of Examples 110 to 113 described above.

115. Further comprising supplying the nozzle heliox 2 with a nozzle heliox 2 pressure between 207 kPa and 414 kPa,
The method according to any one of Examples 110 to 114 described above.

116. Further comprising producing inhalable dry powder aerosol 15 at an inhalable dry powder aerosol pressure of less than 1 water column.
The method according to any one of Examples 110 to 115 described above.

Further comprising producing with an inhalable dry powder aerosol volume flow rate of 91 at 10-15 l / min with a concentration efficiency greater than 117.30%.
The method according to any one of Examples 110 to 116 described above.

118. The aerosol generation system further comprises omitting any flow control device at the cylindrical radial multislit aerosol concentrator outlet 54 of the cylindrical radial multislit aerosol concentrator 24.
The method according to any one of Examples 110 to 117 described above.

119. Further comprising providing a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 79.
The method according to any one of Examples 110 to 118 described above.

Dry powder aerosol aerodynamic center particle diameter (1 Further comprising delivering the drug in the form of solid particles with MMAD),
The method according to any one of the above-mentioned Examples 110 to 119.

Further comprising supplying a solution or suspension with a solution viscosity or suspension viscosity greater than 121.4 cSt,
The method according to Example 120.

122. The method outputs an inhalable dry powder aerosol volume flow rate 91 between 12 l / min and 44 l / min, thereby delivering the drug at a drug mass concentration of at least 5 mg / l and at most 14.5 mg / l. Designed,
The method according to Example 121.

123. Further comprising controlling the volume flow rate ratio such that the ratio of the primary intermediate dry powder aerosol volume flow rate 89 to the inhalable dry powder volume flow rate 91 is less than 5.
The method according to any one of Examples 110 to 122 described above.

124. An aerosol production system for producing an inhalable dry powder aerosol 15 from a solution or suspension.
It has a nozzle input end 11 designed to receive a solution or suspension, a nozzle heliox supply 55 designed to receive a nozzle heliox 2, and a liquid aerosol suspended in the nozzle heliox 2. A liquid aerosol generation nozzle 3 having a nozzle output end 36 for outputting 13 and a nozzle 3
A cylindrical evaporation chamber input end 7 connected to a nozzle input end 36 and a diluted heliox supply unit 60 to receive both the liquid aerosol 13 and the diluted heliox 4 suspended in the nozzle heliox 2, and a primary intermediate dry powder aerosol. A cylindrical evaporation chamber 6 having a cylindrical evaporation chamber output end 8 for outputting 14 at a primary intermediate dry powder aerosol volume flow rate of 89 and a primary intermediate dry powder aerosol particle concentration of 90.
Aerosol generation system.

125. The primary intermediate dry powder aerosol volume flow rate 89 is between 80 l / min and 200 l / min,
The aerosol generation system according to Example 124.

126. The solution or suspension contains a surfactant,
An aerosol generation system according to any one of Examples 124 to 125 described above.

127. The aerosol production system is designed to output a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
An aerosol generation system according to any one of Examples 124 to 126 described above.

128. Aerosol production systems are designed to aerosolize solutions or suspensions with solution or suspension viscosities of 4 to 39 cSt.
An aerosol generation system according to any one of Examples 124 to 127 described above.

129. Nozzle heliox 2 has a nozzle heliox pressure between 207 kPa and 414 kPa.
An aerosol generation system according to any one of Examples 124 to 128 described above.

130. Further comprising a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 95.
The aerosol generation system according to any one of Examples 124 to 129 described above.

131. Aerosol production systems receive solutions or suspensions at a solution volume flow or suspension volume flow of 0.1 to 3 ml / min and a dry powder aerosol aerodynamic center particle of 3 μm or less at a drug mass flow of at least 150 mg / min. Designed to deliver the drug in the form of solid particles with a diameter (MMAD),
An aerosol generation system according to any one of Examples 124 to 130 described above.

132. Aerosol production systems are designed to receive solutions or suspensions with solution viscosities or suspension viscosities greater than 4 cSt.
The aerosol generation system according to Example 131.

133. A method of producing an inhalable dry powder aerosol 15 from a solution or suspension.
The solution or suspension and the nozzle heliox 2 are supplied to the liquid aerosol generation nozzle 3 to supply the solution or suspension.
The liquid aerosol 13 floating in the nozzle heliox 2 is output from the liquid aerosol generation nozzle 3 to the cylindrical evaporation chamber 6.
The diluent gas 4 is supplied to the cylindrical evaporation chamber 6 to supply the diluted gas 4.
From the cylindrical evaporation chamber 6, a primary intermediate dry powder aerosol 14 having fine dry powder particles suspended in a gas, which allows inhalation of particles containing medically effective agents, is provided with a primary intermediate dry powder aerosol volume flow 89 and a primary. Output at an intermediate dry powder aerosol particle concentration of 90,
Method.

134. Includes further production at a primary intermediate dry powder aerosol volume flow rate of 89 between 80 l / min and 200 l / min.
The method according to Example 133.

135. Further comprising adding a surfactant as a component of the solution or suspension,
The method according to any one of the above-mentioned Examples 133 to 134.

136. Further comprising outputting a primary intermediate dry powder aerosol 14 suspended in the gas as fine particles of size 1.5-4 μm MMAD from the cylindrical evaporation chamber 6.
The method according to any one of the above-mentioned Examples 133 to 135.

137. Further comprising aerosolizing a solution or suspension having a solution viscosity or suspension viscosity of 4 to 39 cSt.
The method according to any one of Examples 133 to 136 described above.

138. Further comprising supplying the nozzle heliox 2 with a nozzle heliox 2 pressure between 207 kPa and 414 kPa,
The method according to any one of Examples 133 to 137 described above.

139. Further comprising providing a countercurrent tube 54, an infrared source 39, a reflector 72 and an aerosol recovery cone 79.
The method according to any one of Examples 133 to 138 described above.

Dry powder aerosol with aerodynamic center particle size of 3 μm or less, supplying the solution or suspension at a solution volume flow rate or suspension volume flow rate of 140.0.1 to 3 ml / min and a drug mass flow rate of at least 150 mg / min. Further comprising delivering the drug in the form of solid particles with MMAD),
The method according to any one of Examples 133 to 139 described above.

Further comprising supplying a solution or suspension with a solution viscosity or suspension viscosity greater than 141.4 cSt.
The method according to any one of Examples 133 to 140 described above.

Nozzle gas 2
Liquid aerosol generation nozzle 3
Diluted gas 4
Flow distributor 5
Cylindrical evaporation chamber 6
Cylindrical evaporation chamber input end 7
Cylindrical evaporation chamber output end 8
Cylindrical linear single slit aerosol concentrator 9
Cylindrical Linear Single Slit Aerosol Concentrator Input End 10
Nozzle input end 11
Liquid aerosol 13
Primary intermediate dry powder aerosol 14
Inhalable dry powder aerosol 15
Primary emission aerosol 16
Secondary intermediate dry powder aerosol 17
Convergent Cylindrical Linear Single Slit Aerosol Concentrator Input Path 19
Cylindrical Linear Single Slit Aerosol Concentrator Input Orifice 20
Cylindrical Linear Single Slit Aerosol Concentrator Output Orifice 21
Divergent Cylindrical Linear Single Slit Aerosol Concentrator Output Path 22
Cylindrical radial multi-slit aerosol concentrator 24
Cylindrical radial multi-slit aerosol concentrator input end 25
Cylindrical radial multi-slit aerosol concentrator output end 26
Nozzle holder 27
Central flow path 28
Liquid nozzle 29
Gas inlet orifice 30
Gas flow path 31
Circular pressure balancing chamber 32
Circular convergent flow path 33
Circular divergence flow path 34
Aerosolized space 35
Nozzle output end 36
Aerosol eruption 37
Countercurrent orifice 38
Infrared source 39
Cylindrical linear single slit aerosol concentrator aerosol separation space 40
Circular exit 41
Sculpture Plenum 43
Cylindrical Linear Single Slit Aerosol Concentrator Outlet 44
Acceleration nozzles 45 arranged in a radial pattern
Radially aligned deceleration nozzles 46
Acceleration slit orifice 47
Deceleration slit orifice 48
Cylindrical radial multi-slit aerosol concentrator Aerosol separation space 49
Circular plenum 50
Cylindrical radial multi-slit aerosol concentrator outlet 51
Convergent Cylindrical Linear Single Slit Aerosol Concentrator Input Path Angle 52
Divergent Cylindrical Linear Single Slit Aerosol Concentrator Output Path Angle 53
Countercurrent tube 54
Nozzle gas supply unit 55
Channel 56
Compressed gas flow path 57
Stenosis orifice 58
Countercurrent flow path 59
Diluted gas supply unit 60
Donut type chamber 61
Hole in the first baffle 62
First baffle 63
Second circular chamber 64
Second baffle 65
Internal cylindrical chamber hole 66
Internal cylindrical chamber 67
Central hole 68
Peripheral hole 69
Quartz tube 70
Semi-cylindrical aluminum reflector 72
Lip seal 73
Convergent Cylindrical Linear Single Slit Aerosol Concentrator Input Orifice Angle 74
Divergent Cylindrical Linear Single Slit Aerosol Concentrator Output Orifice Angle 75
Outer surface of convergent flow path 76
Outer surface of divergent flow path 77
Inner wall 78
Recovery cone 79
Engraving discharge channel 80
Entrance plate 81
Inlet plate flow path 82
Back plate 83
Back plate flow path 84
Convergent discharge channel 85
Secondary emission aerosol 86
Primary Intermediate Dry Powder Aerosol Volume Flow 89
Primary intermediate dry powder aerosol particle concentration 90
Inhalable dry powder aerosol volumetric flow rate 91
Inhalable dry powder aerosol particle concentration 92
Secondary Intermediate Dry Powder Aerosol Volume Flow 93
Secondary intermediate dry powder aerosol particle concentration 94
Two-stage concentrator 96

Claims (15)

Inhalable Dry Powder Aerosol An aerosol generation system for producing an inhalable dry powder aerosol (15) from a solution or suspension at a volumetric flow rate (91).
Said solution or said suspension, nozzle gas (2) and liquid aerosols suspended in the receiving diluent gas (4) nozzle gas (2) (13) and said configured to output a diluent gas (4) Liquid Aerosol generation unit and
A cylindrical evaporation chamber (6) having a cylindrical shape.
Connected to the liquid aerosol generation unit so as to receive both the liquid aerosol (13) and the diluted gas (4) floating in the nozzle gas (2) at one end of the cylindrical evaporation chamber (6) in the axial direction. has been has cylindrical evaporation chamber input (7),
The primary intermediate dry powder aerosol (14) is output to the other end of the cylindrical evaporation chamber (6) in the axial direction at the primary intermediate dry powder aerosol volume flow rate (89) and the primary intermediate dry powder aerosol particle concentration (90) . Has a cylindrical aerosol chamber outflow end (8) ,
Cylindrical evaporation chamber (6) and
A cylindrical linear single-slit aerosol concentrator (9) having a cylindrical shape and arranged coaxially with the cylindrical evaporation chamber (6) , the shaft of the cylindrical linear single-slit aerosol concentrator (9). In order along the direction,
A cylindrical linear single-slit aerosol concentrator input end (10) connected to the cylindrical evaporation chamber output end (8) and having a circular cross-sectional shape of the internal cavity.
From the cylindrical linear single-slit aerosol concentrator input end (10), the internal cavity extends in the axial direction of the cylindrical linear single-slit aerosol concentrator (9) while converging so that the circular cross section is reduced in diameter. Convergent cylindrical single-slit aerosol concentrator input path (19) forming a cylindrical linear single-slit aerosol concentrator input orifice (20), which is a linear single slit at the converged tip.
From the cylindrical linear single-slit aerosol concentrator output orifice (21), which is a linear single slit arranged so as to face parallel to the cylindrical linear single-slit aerosol concentrator input orifice (20), an internal cavity is formed. A divergent cylindrical single-slit aerosol concentrator output path (22) extending in the axial direction of the cylindrical linear single-slit aerosol concentrator (9) while diverging so as to have a circular cross section and a larger diameter.
Cylindrical linear single-slit aerosol concentrator (9)
With
By arranging the cylindrical linear single-slit aerosol concentrator input orifice (20) and the cylindrical linear single-slit aerosol concentrator output orifice (21) at intervals, the cylindrical linear single-slit aerosol concentrator Between the input orifice (20) and the cylindrical linear single-slit aerosol concentrator output orifice (21), there is a cylindrical linear single-slit aerosol concentrator aerosol separation space (40) that communicates fluidly with the outside of the aerosol generation system. Formed ,
Aerosol generation system. At least one of the nozzle gas (2) and the diluent gas (4) is heliox or air.
The aerosol generation system according to claim 1. The primary intermediate dry powder aerosol volume flow rate (89) is between 80 l / min and 200 l / min.
The aerosol generation system according to claim 1 or 2. The cylindrical linear single-slit aerosol concentrator output orifice (21) has a longitudinal dimension of the slit between 1 cm and 5 cm and a lateral dimension of the slit between 1 mm and 2 mm.
The aerosol generation system according to any one of claims 1 to 3. The convergent cylindrical single-slit aerosol concentrator input path (19) is from the cylindrical linear single-slit aerosol concentrator input end (10) to the cylindrical linear single-slit aerosol concentrator input orifice (20). Convergent cylindrical single-slit aerosol concentrator input path angle (52) between 10 and 60 degrees towards the center of
The divergent cylindrical single-slit aerosol concentrator output path (22) is a divergent cylindrical linear shape between 10 and 60 degrees from the cylindrical linear single-slit aerosol concentrator output orifice (21). Single-slit aerosol concentrator diverges at output path angle (53),
The aerosol generation system according to any one of claims 1 to 4. The cylindrical linear single-slit aerosol concentrator input orifice (20) and the cylindrical linear single-slit aerosol concentrator output orifice (21), which are the widths of the cylindrical linear single-slit aerosol concentrator aerosol separation space (40). ) Is less than 2 mm,
The aerosol generation system according to any one of claims 1 to 5. The cylindrical linear single-slit aerosol concentrator aerosol separation space (40) is in a space (43) closed by a wall (76,77,78).
A cylindrical linear single-slit aerosol concentrator discharge port (44), which is a hole for fluid communication of the space (43) with the outside of the aerosol generation system, is formed on the wall (78).
The diameter of the cylindrical linear single-slit aerosol concentrator outlet (44) is 10 to 20 mm.
The aerosol generation system according to any one of claims 1 to 6. The aerosol generation system has no flow control device at the cylindrical linear single-slit aerosol concentrator discharge port (44) of the cylindrical linear single-slit aerosol concentrator (9).
The aerosol generation system according to claim 7. The cylindrical linear single-slit aerosol concentrator discharge port (44) is in the longitudinal direction of the cylindrical linear single-slit aerosol concentrator input orifice (20) and the cylindrical linear single-slit aerosol concentrator output orifice (21). Aligned with the axis,
The aerosol generation system according to claim 7 or 8. A method for producing an inhalable dry powder aerosol (15) from a solution or suspension at a volumetric flow rate (91) of an inhalable dry powder aerosol using the aerosol generation system according to any one of claims 1 to 9. And
Solutions or suspensions, by supplying nozzle gas (2) and diluent gas (4) to the liquid aerosol generating unit, the aerosol generating unit, the liquid aerosol (13) floating in the nozzle gas (2) and the diluent gas (4) is output to a cylindrical evaporation chamber (6) in the said the cylindrical evaporation chamber (6), the particles comprising a medically active agent to enable inhalation, fine dry powder suspended in a gas the primary intermediate dry powder aerosol having a particle (14), supplied to the primary intermediate dry powder aerosol volume flow (89) and the cylindrical linear single slit aerosol concentrator in primary intermediate dry powder aerosol particle concentration (90) (9) The divergent cylindrical linear single-slit aerosol concentrator output path (22) has the inhalable dry powder aerosol volume flow rate (91) lower than the primary intermediate dry powder aerosol volume flow rate (89) and the primary. The inhalable dry powder aerosol (15) is output at an inhalable dry powder aerosol particle concentration (92) higher than the intermediate dry powder aerosol particle concentration (90).
Method. Further comprising supplying heliox or air as at least one of the nozzle gas (2) and the diluent gas (4).
The method according to claim 10. Further comprising adding a surfactant as a component of the solution or suspension.
The method according to claim 10 or 11. Further comprising supplying the solution or suspension having a solution viscosity or suspension viscosity of 4 to 39 cSt.
The method according to any one of claims 10 to 12. Supplying the solution or suspension at a solution volume flow rate or suspension volume flow rate of 0.1 to 3 ml / min.
Further comprising supplying the solution or suspension with a solution viscosity or suspension viscosity greater than 4 cSt.
The method according to any one of claims 10 to 13. Arranging the aerosol generation system so that the longitudinal direction of the slits of the cylindrical linear single-slit aerosol concentrator input orifice (20) and the cylindrical linear single-slit aerosol concentrator output orifice (21) is vertical. Including,
The method according to any one of claims 10 to 14.

Images